Originally published online as doi:10.1189/jlb.0907650 on April 3, 2008

Published online before print April 3, 2008

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(Journal of Leukocyte Biology. 2008;84:1-26.)
© 2008 by Society for Leukocyte Biology

Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS

Alexandre Iannello, Olfa Debbeche, Suzanne Samarani and Ali Ahmad¹

Laboratory of Innate Immunity, Center of Research Ste Justine Hospital, and Department of Microbiology and Immunology, University of Montreal, Montreal, Quebec, Canada

¹Correspondence: Center of Research, Ste Justine Hospital, 3175 Côte Ste-Catherine, Montreal, Qc, H3T 1C5, Canada. E-mail: ali.ahmad{at}recherche-ste-justine.qc.ca

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
NK cells play an important role in controlling viral infections. They can kill virus-infected cells directly as well as indirectly via antibody-dependent, cell-mediated cytotoxicity. They need no prior sensitization and expansion for this killing. NK cells are also considered as important regulators of antiviral immune responses. They do so by secreting a multitude of soluble mediators and by directly interacting with other immune cells, e.g., dendritic cells. NK cells do not possess a single well-defined receptor to recognize antigens on target cells. Instead, they express an array of inhibitory and activating receptors and coreceptors, which bind to their cognate ligands expressed on the surface of target cells. These ligands include classical and nonclassical MHC class I antigens, MHC-like proteins, and a variety of other self- and virus-derived molecules. They may be expressed constitutively and/or de novo on the surface of virus-infected cells. NK cell receptors (NKRs) of the killer-cell Ig-like receptor (KIR) family, like their MHC class I ligands, are highly polymorphic. Several recent studies suggest that epistatic interactions between certain KIR and MHC class I genes may determine innate resistance of the host to viral infections, including HIV. In the first part of this review article, we provide an overview of the current state of knowledge of NK cell immunobiology and describe how NKR genes, alone and in combination with HLA genes, may determine genetic resistance/susceptibilty to HIV infection and the development of AIDS in humans.

Key Words: CD94/NKG2 • chemokines • cytokines • HIV-1 • HLA • KIR • KIR haplotypes • MHC class I • MICA • MICB • NKG2D • ULBP

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
HIV is the causative agent of AIDS: a dreadful and socially stigmatizing disease syndrome of the 20th century that inevitably leads to death. The AIDS epidemic has killed more than 25 million humans since 1981. At present, close to 40 million people are infected with the virus in the world. It has been estimated that in 2006, more than 4 million new infections occurred with the virus, and 3 million people died of AIDS in the world. It is widely believed that the viral infection is spreading in several underdeveloped and developing countries, e.g., China, India, and Eastern European countries (www.unaids.org). This situation underlines the need for developing an effective anti-HIV vaccine. However, at present, the prospects of developing an effective anti-HIV vaccine do not seem very promising. Although, anti-HIV drugs have significantly prolonged lifespans of HIV-infected patients and have reduced deaths, they do not cure the infection. Furthermore, sooner or later, the virus develops resistance to these drugs. Researchers have made spectacular advances in studying and analyzing immune responses to the virus. Most of these studies have largely focused on virus-specific immunity, i.e., HIV-specific antibodies, CD4⁺ and CD8⁺ T cell responses. It is noteworthy that the inductive and effector mechanisms of these responses depend on the recognition of small viral peptides by the immune cells. Unfortunately, small RNA viruses (such as HIV) are quite apt in neutralizing these responses by their remarkable ability to mutate (reviewed in ref. [¹ ]). On the other hand, innate immune responses do not limit themselves to the recognition of small viral peptides. Instead, innate immune cells recognize so-called molecular patterns associated with pathogens (e.g., dsRNA, CpG motifs in viral DNA), altered self (reduced expression of MHC antigens), and/or induced self (de novo expression of pathogen-induced host proteins) on the body’s own cells. Activation of innate immune cells is also a prerequisite for mounting an effective, pathogen-specific adaptive immunity. Understanding these responses may provide better ways of controlling viral infections.

NK cells constitute an important component of the host’s innate immune system. Once considered as relatively unimportant and nonspecific killers of tumor cells, NK cells are now recognized as important cells with ready-to-go effector and regulatory functions. For long, NK cells have been known to kill virus-infected cells, and NK cell-deficient individuals have been known to suffer from repeated viral and bacterial infections [² , ³ ]. However, a lack of understanding of NK cell immunobiology until recent years has been an impediment in appreciating the role of these cells in controlling these infections. Today, scientists have made significant advances in understanding how NK cells function and regulate innate and adaptive immune responses. Consequently, we have learned a lot about the role of these cells in HIV and other viral infections. The review focuses on NK cell responses in HIV infections and their relevance to anti-HIV resistance, immunotherapy, and vaccination. We also underline some of the important unresolved issues with respect to these cells in HIV infection that need to be addressed in future research. Understandably, it will have to begin with an overview of the current immunobiology of NK cells.

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
NK cells are a population of low-density, large granular lymphocytes, which mainly develop and differentiate in bone marrow and then enter into the circulation. Significant numbers of NK cells also develop and differentiate in thymus, spleen, tonsils, and lymph nodes [⁴ , ⁵ ]. As a result of their different sites and pathways of development, NK cells are heterogeneous with respect to their phenotypic characteristics and functional capabilities. They make up 10–15% of the PBMC. In response to proinflammatory stimuli, which may be induced by a viral infection, NK cells migrate to various tissues and organs of the body. Significant numbers of NK cells occur in thymus, lymph nodes, gut, liver, peritoneum, and other organs and tissues of the body. NK cells represent a cell lineage distinct from those of monocytes, granulocytes, and B cells. They share a common hematopoietic progenitor with T cells. However, they are less specialized than T cells and retain certain ancestral characteristics of plasticity and versatility. Phenotypically, NK cells are CD3^–, CD2⁺, CD16⁺, CD56⁺, CD14^–, and CD19^–. Unlike T and B cells, they do not express a well-defined single antigen receptor. They also do not express recombinase activating genes (RAG) and retain their TCR and BCR genes in germ-line configurations. See Table 1 for commonly used NK cell markers. It is noteworthy that most of these markers are not NK cell-specific, as cells of other types may also express them. However, NKp46 and NKp30 may be considered as NK cell-specific markers, as non-NK cells rarely express them.

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Table 1. Common Markers Used for Phenotypic Characterization of Human NK Cells

NK cells should not be confused with NKT cells. The two cell types are quite distinct from each other with respect to their origin, phenotype, antigen recognition, and certain effector functions (reviewed in refs. [⁶ , ⁷ ]). As their name implies, NKT cells share characteristics with NK and T cells; i.e., they are CD3⁺, bear clonotypic β TCR and certain NK cell markers (CD56⁺, CD161⁺), and secrete IFN- and/or IL-4. They recognize self and foreign glycolipids in association with a MHC class I-related glycoprotein CD1d. Activation of NKT cells usually leads to activation of NK cells and dendritic cells (DC) in the body.

Human NK cells can be divided into two major subsets based on the level of expression of CD56 and the presence or absence of CD16. The two markers are usually expressed reciprocally on these cells. The two subsets CD56^highCD16^– and CD56^lowCD16⁺ represent 10% and 90% of NK cells present in the peripheral blood, respectively [⁸ , ⁹ ]. The cells in the two subsets differ in their proliferative potential, homing characteristics, functional capabilities, and responses to different cytokines (listed in Table 2 ). The cells in the former subset express high-affinity receptors for IL-2, proliferate in response to picomolar concentrations of the cytokine, produce mainly cytokines upon activation, and have low cytotoxic potential. They express little KIR and preferentially migrate to secondary lymphoid organs, e.g., lymph nodes, tonsils. Most of the NK cells in lymph nodes are CD56^high. The CD56^low CD16⁺ NK cells express low-affinity IL-2Rs, proliferate in response to nanomolar concentrations of IL-2, express KIR, and are highly cytotoxic. These NK cells migrate to inflamed tissues in response to chemotactic stimuli. By virtue of expression of CD16, they are also efficient mediators of ADCC. The CD56^high subset is less cytotoxic as compared with the CD56^low subset, probably as a result of their lower expression of perforin and -chain [⁹ , ¹⁰ ]. The -chain is a signal-transducing component of the high-affinity receptor for IgE (FcRI) and acts as a signaling partner for several activating NK cell receptors (NKRs), e.g., CD16a, NKp30, NKp46, etc. Both NK cell subsets become potent killer cells upon incubation with cytokines and are called lymphokine-activated killer cells. Some workers also differentiate between CD16^high and CD16^dim subsets of NK cells. Furthermore, NK cells expressing CD56 and CD16 have also been described. They may represent different activation and differentiation states of NK cells. It is noteworthy that incubation with different cytokines may change phenotypic, functional, as well as homing characteristics of NK cells. For example, IL-2, IL-12, and IL-15 can convert CD56^highCD16^– and CD56^lowCD16⁺ NK cell subsets into CD56^brightCD16⁺ cells. On the other hand, TGF-β1 converts CD16⁺ NK cells into CD16^– NK cells [^{11 12 13} ].

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Table 2. Characteristics of Two Major NK Cell Subsets

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
Although NK cells have been traditionally known for their ability to kill certain tumor and virus-infected cells, they also perform other important roles (detailed in Table 3 ). Like neutrophils, NK cells can kill bacteria by secreting -defensins: the antimicrobial peptides that can disrupt bacterial cell walls. They act as important immunoregulatory cells by secreting cytokines and chemokines. It is noteworthy that NK cells are the only known source of IFN- other than activated T cells. The cytokine is known to activate macrophages and drive CD4⁺ T cell differentiation into type 1 (TH1) cells. It also induces expression of TRAIL on T cells. An immediate release of this cytokine from NK cells in early stages of an infection is crucial for inducing virus-specific immunity. In addition to IFN-, NK cells have been documented to secrete TNF-, GM-CSF, IL-5, IL-13, IL-10, TGF-β, MIP-1, MIP-1β, RANTES, NO, etc. (reviewed in ref. [¹⁴ ]). In addition to their immunoregulatory properties, IFN- and TNF- can induce an antiviral state in the host cells and inhibit virus replication by noncytopathic mechanisms. This virtual curing of the infected cells is increasingly being appreciated in controlling viral infections [¹⁵ ].

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Table 3. NK Cell Functions

NK cells regulate immune responses by interacting physically with other cells in the body. Their interactions with monocyte-macrophages, DC, and T, B, NKT, and vascular endothelial cells are beginning to be understood. These interactions bear important implications for viral infections, malignancy, and autoimmunity. Under appropriate conditions, NK cells can cause differentiation of monocytes into macrophages [¹⁶ ]. They also interact with activated macrophages. These interactions result into activation of interacting NK cells via 2B4 and CD48 interactions. NK cells also kill macrophages that become overactive (with high doses of LPS) and express de novo ligands for certain activating NKRs. They also kill macrophages, which produce immunosuppressive, cytokine-like TGF-β and IL-10. Consequently, NK cells promote TH1 responses needed for the induction of an effective immune response against intracellular pathogens [¹⁷ , ¹⁸ ]. Interestingly, NK cells themselves have the potential to act as APC. It may be relevant to mention here that a special kind of cell was described in mice with DC and NK cell-type characteristics. It was named as IFN-producing killer DC (IKDC), which kill virus-infected cells as well as tumor cells, produce IFNs, and present antigens to T cells [^{19 20 21} ]. The IKDC, in fact, represent a distinct activation stage of NK cells [²² ]. Such cells have not been found in humans. However, it is argued that the human immune system is more developed than that of mice, and all human NK cells can act as APC under appropriate conditions. Activated human NK cells express several molecules, which enable them to interact with T cells, e.g., CD11c, MHC class II, CD80, CD86, CCR7, CD70, etc. Incubation of NK cells with IL-18 has been shown to enhance their helping functions [²³ ]. This NK cell "help" function is supported by the reports that in the presence of activated NK cells, antigen-specific CTL may be generated without help from CD4⁺ T cells [²⁴ ].

NK cell–DC interactions are complex and are important for innate and adaptive immune responses against viral infections. They will be discussed in a later section in this article.

NK cell interactions with other immune cells are important for the induction of effective immune responses. It has been shown that NK cells can regulate adaptive CD4⁺ memory T cells. More specifically, adoptive transfer of CD4⁺ memory T cells specific for myelin oligodendrocyte glycoprotein (MOG; an autoantigen) is able to expand and cause experimental autoimmune encephalitis (EAE; a mouse model of multiple sclerosis) in RAG-2-deficient mice, which lack T and B cells but have functional NK cells. However, NK cells in these mice are inhibited from killing the CD4⁺ memory T cells, as the latter expresses Qa-1 (the mouse equivalent of human HLA-E). The transferred cells do not cause EAE in Qa-1 lacking mice. NK cells kill MOG-specific CD4⁺ memory T cells in these mice. These results show that NK cells play an important role in the homeostasis of memory T cells and may also eliminate autoreactive CD4⁺ memory T cells under appropriate conditions. The results suggest that blocking Qa-1/NKG2A interactions may represent a better clinical strategy to eliminate autoreactive T cells than using anti-CD3 antibodies [²⁵ ].

In certain mouse models, NK cell activation has been shown to be indispensable for inducing antitumor antibody and CTL responses [¹⁷ , ²⁶ ]. In addition to producing IFN-, physical interactions between NK cells and other immunocytes are needed for these responses. For example, via CD40/CD40L interactions, NK cells can induce transcription of activation-induced cytidine deaminase and switch recombinations in B cells [²⁷ ].

NK cells are plastic and may differentiate themselves into cell types that produce predominantly IFN- or IL-5. It is not known what causes this polarization in NK cells. It has also been suggested that these differences in cytokine production may result from their different differentiation states. Nevertheless, this polarized production of cytokines from NK cells may be correlated with certain disease conditions. For example, IL-5- and IFN--producing NK cells were shown to correlate with remissions and relapses in multiple sclerosis in humans, respectively [²⁸ ]. The NK cells producing predominantly IL-5 also expand and play a role in asthma in humans [²⁹ ].

In a provocative study, NK cells were shown to mediate memory-type responses. In RAG–/– mice, which lack T and B cells, O'Leary et al. [³⁰ ] demonstrated NK cell-dependent, anamnestic responses to a hapten in mediating contact hypersensitivity. Although the molecular mechanisms behind this NK cell-dependent memory are not clear, the results may have important implications for development of vaccines.

NK cells play an important role in successful pregnancy and reproductive efficiency. The KIR2DL4/HLA-G interactions and consequent secretion of IFN- from uterine NK cells are needed for placentation [³¹ , ³² ].

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
NK cells exist in the body in a semi-activated state and are ready to kill susceptible target cells. However, they may undergo activation in vitro and in vivo, which enhances their functional capabilities. Various stimuli that activate NK cells are listed in Table 4 . A variety of cytokines activates NK cells and induces their proliferation as well. Activated NK cells have increased expression of activating receptors, adhesion molecules, and intracellular effector molecules, e.g., perforin. They secrete higher amounts of cytokines and have higher cytolytic potential and a reduced threshold to trigger their killing mechanism. Virus-induced cytokines usually result in activation of NK cells of the host. These cytokines include IFN-/β, IL-2, IL-12, IL-15, IL-18, IL-21, and others [¹⁴ , ³³ ]. Of these cytokines, IL-15, IL-21, and fms-like tyrosine kinase 3 ligand have been found to be essential for the development, differentiation, and homeostasis of NK cells. IL-15 knockout (KO) mice are deficient in NK cells. Furthermore, NK cells from normal mice undergo apoptosis when transfused into IL-15 KO mice (reviewed in ref. [³⁴ ]).

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Table 4. How NK Cells Become Activated in Viral Infections

NK cells also express TLRs. Therefore, they can undergo activation upon binding with certain viral proteins and nucleic acids via these receptors [³⁵ , ³⁶ ]. However, NK cells require accessory cell function (presence of CD14⁺ monocytes or plasmacytoid DC) for TLR-mediated activation [^{37 38 39} ]. Certain viral proteins may act as ligands for one or more activating NKRs and therefore, may directly activate NK cells; e.g., HA of the influenza virus activates NK cells via NKp46 and NKp44 [⁴⁰ ]. NK cells also become activated when they contact a susceptible target cell (e.g., K562, which has reduced expression of MHC class I and/or has increased expression of ligands for certain activating NKRs) and trigger their cytolytic machinery to kill the target cell.

NK cells mainly kill their target cells by releasing cytotoxic molecules (perforin, granzymes, and granulysin), which are normally contained in their granules. These molecules are released within the immune synapse (IS) onto the surface of the target cells. NK cells can also kill target cells by FasL, TRAIL, and TNF- if the target cells express appropriate receptors [⁴¹ , ⁴² ]. NK-cell mediated lysis is usually determined in microcytotoxicity assays by measuring the release of ⁵¹chromium, lactate dehydrogenase, or perforin in culture supernatants. Individual NK cells mediating the lysis can be recognized and counted by detecting the expression of lysosomal protein lysosome-associated membrane protein-1 (CD107a) on their surface [⁴³ , ⁴⁴ ].

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
As mentioned above, NK cells mainly kill their target cells via releasing cytotoxic granules. To avoid unintended damage to neighboring cells, NK cells release these effector molecules in a well-defined and restricted area of contact with the target cells (reviewed in ref. [⁴⁵ ]). This area of contact between the two cells is called IS. The synapse is an activating one if it is formed between a NK cell and a susceptible target cell. The formation of the synapse is initiated by interaction between different activating receptors and adhesion molecules (e.g., CD2, LFA-1, CD11a, CD11b) on NK cells and their cognate ligands on the target cell. The adhesion molecules aggregate in the form of a ring at the periphery of the synapse (Fig. 1 ). The engagement of integrins causes their activation and results in talin-mediated actin polymerization. The close contact between NK and target cell membranes induces reorientation of the MTOC of the NK cell toward the synapse. The microtubule-associated motor proteins (kinesins) shuttle granules containing cytotoxic mediators toward the center of the synapse. Within the center of the synapse, different activating NKRs interact with their cognate ligands on the target cell. The glycosphingolipid-rich membrane microdomains (lipid rafts) rapidly accumulate in the center of the synapse in a cytoskeleton-dependent manner. The lipid rafts are rich in effector signaling molecules. Their recruitment to the synapse requires activities of several kinases (Src, Syk, and the serine-threonine kinase protein kinase C). A ring of F actin surrounds the center of the synapse and prevents spillover of the cytotoxic mediators from the synapse. Within the synapse, NK and target cells interact with each other via membranous protrusions, which end at coated pits on the surface of opposing cells [⁴⁶ ]. The Src homology 2 (SH2) domain-containing phosphatase (SHP)-1 is recruited to the periphery of the synapse within 1 min. It limits the activation event to the center of the synapse. Actin polymerization and MTOC reorganization are key events needed to trigger NK cell cytotoxicity (degranulation). The pharmacological agents that inhibit actin polymerization also inhibit NK cell-mediated killing [⁴⁷ ]. Another phosphatase, SHIP, is also recruited to the synapse within minutes to terminate the triggering of the NK cell. After discharging its cytotoxic mediators to the membrane of the target cell, the NK cell separates itself and is ready to kill another target cell. A single NK cell can kill several target cells in a sequence one after the other. The inhibitory IS is formed between an NK cell and a resistant target cell. Its formation is prevented at an early stage by inhibitory receptor-recruited phosphatases. The inhibitory receptors cluster in discrete microdomains in the center of the inhibitory synapse and interact with their cognate ligands.

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Figure 1. Formation of IS between NK and target cells. Various NKRs interact with their cognate ligands on the target cell in the center of the synapse, which contains lipid rafts and activating NKRs. The adhesion molecules [CD2, LFA-1, membrane-activated complex 1 (MAC-1)] bind to their cognate ligands on the target cell and aggregate in the form of a ring. Activation of integrins leads to talin-mediated actin polymerization. The close contact between NK and target cell membranes induces reorientation of the microtubule-organizing center (MTOC) of the NK cell toward the synapse. The microtubule-associated motor proteins (kinesins) shuttle granules containing cytotoxic mediators toward the center of the synapse. Within the center of the synapse, different activating NKRs interact with their cognate ligands on the target cells. A ring of F actin surrounds the center of the synapse, preventing the spillover of the cytotoxic mediators from the synapse. T and NK indicate target cell and NK cell, respectively. C and P represent center and periphery of the synapse. WASP, Wiskott-Aldrich syndrome protein; PTK, protein tyrosine kinase; SYK, spleen tyrosine kinase; SRC, sarcoma tyrosine kinase.

A characteristic feature of the activating IS is exchange of membrane proteins (receptors, ligands, adhesion molecules, etc.) between the interacting cells. For example, NK cells may transfer inhibitory KIR to target cells. The latter cell types may transfer MHC-class I chain-related protein A (MICA) to NK cells, which in turn, may transfer these acquired proteins to other NK cells via homotypic, intercellular contacts [⁴⁸ , ⁴⁹ ].

NK cells, like other immune cells, can also communicate with other cells at a distance by forming nanotubules and transfer molecules and Ca⁺⁺ fluxes to them (reviewed in ref. [⁵⁰ ]).

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
NKRs and coreceptors regulate NK cell-mediated killing. They include a variety of molecular structures expressed on the surface of NK cells. They bind specific ligands on target cells. NKRs can be divided into inhibitory and stimulatory types depending on the nature of the signal they send to NK cells after binding to their specific ligands. Each NK cell expresses inhibitory and stimulatory NKRs. Target cells may vary from one another with respect to the level of expression of ligands for different NKRs. According to the prevalent wisdom, triggering of an NK cell depends on the balance between inhibitory and stimulatory signals that it receives from the target cell via NKR (see Fig. 2 ). A NK-sensitive target cell usually would express one or more ligands for activating NKR, whereas a NK-resistant target cell would express more ligands for inhibitory receptors and/or may lack ligands for activating NKR. The human NKR can be divided into MHC and non-MHC-binding receptors.

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Figure 2. Model for NK cell-mediated killing of virus-infected cells. Normal cells express ligands (usually MHC class I molecules) for inhibitory receptors of NK cells and are resistant to NK cell-mediated killing (top panel). Viral infections may reduce the expression of these inhibitory ligands on the infected cells and make them susceptible to killing by NK cells (middle panel). They may further induce expression of ligands for activating NKRs (e.g., for NKG2D) and make them super-susceptible to the killing (bottom panel).

MHC-binding receptors
They include KIR, NKG2, and Ig-like transcript (ILT) families. They are discussed below.

KIR (CD158) family
The KIR are type I integral membrane glycoproteins that are usually expressed as monomers on the cell surface [^{51 52 53} ]. At present, 14 distinct KIR genes and two pseudogenes have been described (see http://www.ebi.ac.uk/ipd/kir for an update on KIR genes and alleles). They are located on human chromosome 19q13.4 in a tandem head-to-tail manner in a short, 150-kb region, called leukocyte receptor complex (LRC). KIR genes show extensive allelic polymorphism. For example, KIR2DL1 and KIR3DL1 genes have at least 14 and 47 alleles, respectively. Their transcripts also undergo alternate splicing, giving rise to distinct receptor variants. It has been estimated that after MHC, KIR is the most polymorphic locus in humans. KIR genes are not present in mice, suggesting their recent evolution after divergence of the two species 5 million years ago. They are undergoing rapid evolution in humans under pressure from pathogens, malignancy, and autoimmunity. Two human populations living next to each other and having similar HLA genes frequently differ with respect to their KIR genes. This observation suggests that the latter genes are evolving faster than the former ones.

KIR structure.
A typical KIR gene contains nine exons as illustrated in Figure 3 . The exons encode leader sequence (exons 1 and 2), extracellular Ig-like domains (D0, D1, and D2; exons 3–5), stem (exon 6), transmembrane region (exon 7), and cytoplasmic tail (exons 8 and 9) of the KIR. The two-domain KIR lack an extracellular domain (D0 or D1). The ones lacking D0 (KIR2L1, KIR2DL2/3) are called type I KIR, whereas the ones lacking D1 (KIR2DL4 and KIR2DL5; see below) are called type II KIR. The structure of a typical KIR gene along with the receptor is shown in Figure 3 . The extracellular region of the receptor binds with its ligand and consists of two or three Ig-like domains. The cytoplasmic tail transduces receptor-initiated signals. Depending on the length of the cytoplasmic tail, a KIR could be short-tailed (S) or long-tailed (L). The L forms are usually inhibitory KIR and have two ITIMs (with canonical sequence I/VxYxxL) in their cytoplasmic tails, as depicted in Figure 4 . Upon binding to their ligands, the tyrosine residues in the ITIMs become phosphorylated and recruit SHP-1 and -2. These phosphatases dephosphorylate several substrates involved in the NK cell activation cascade, e.g., Vav, -associated protein 70 (Zap-70), Syk, phospholipase C (PLC)-1, Shc, and SH2 domain-containing leukocyte protein of 76 kDa, and inhibit the NK cell from triggering its cytotylic machinery and secreting cytokines. The receptors with a short (S) cytoplasmic tail are stimulatory. They lack ITIMs but possess a positively charged amino acid (lysine) in their transmembrane regions. Via this amino acid, they associate noncovalently with a dimer of an adaptor protein, killer cell-activating receptor-associated protein (KARAP) or DAP-12 [⁵⁴ ]. Each DAP-12 carries ITAMs [with canonical sequence D/Ex(0–2)YxxL/Ix(6–8)YxxL/I] in its cytoplasmic tail. When an activating KIR binds to its ligand, the tyrosine residues in the ITAMs are phosphorylated and recruit various tyrosine kinases, e.g., Syk and Zap-70, and send activating signals to NK cells to kill target cells and secrete cytokines. The signals converge to phosphorylate Vav, which is a guanine nucleotide exchange factor (GEF) and activates the Rho family of small GTPases. Upon activation, the GTPases cause actin polymerization, cytoskeleton rearrangement, and triggerring of degranulation (reviewed in ref. [⁴⁵ ]).

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Figure 3. Structure of a typical KIR gene and its encoded receptor. A typical KIR gene comprises nine exons shown here on the right side of the figure. Double horizontal lines in the gene indicate introns. The schematic structure of the encoded receptor is shown on the left. The part of the receptor encoded by each individual exon is also indicated. The scissor in the figure indicates cleavage site for the signal peptide. The letters N and C designate N- and C-terminals of the protein, respectively; not drawn to the scale. D0, -1, -2, Extracellular Ig-like domains; TM, transmembrane region.

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Figure 4. MHC-binding NKRs. The figure shows the schematic structures of main MHC-binding receptors: KIR, ILT-2, and CD94/NKG2. The ligands for the receptors are also shown on the top of each receptor; not drawn to the scale. DAP-12, Dynax activation protein 12.

The KIR are named, depending on the number of Ig-like domains (2 or 3) present in the extracellular region as well as the length of the cytoplasmic tail (L or S). Each KIR gene and its alleles are given different numbers. The KIR expressed in humans, their signaling partners, and ligands are given in Table 5 .

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Table 5. Human KIR (CD158) and Their Ligands

Two-domain KIR and their ligands.
KIR bind to supertypic public determinants expressed by a subset of closely related HLA or MHC class I antigens. The two-domain receptors (e.g., KIR2DL1, KIR2DL2/3) bind to HLA-C antigens. It is noteworthy that all HLA-C antigens show a dimorphism at position (p)80 in the amino-acid sequences of their -2 helices: They have asparagine or lysine. The HLA-C with an asparagine at p80 (e.g., HLA-Cw2, -4, -5, -6, -17, and -18) are called group I HLA-C, whereas the ones with a lysine at p80 (e.g., HLA-Cw1, -3, -7, -8, -13, and -14) are called group II HLA-C. The KIR2DL1 binds group II HLA-C, and KIR2DL2 and its allelic variant (KIR2DL3) bind group I HLA-C [⁵³ , ^{55 56 57 58} ] (reviewed in refs. [⁵³ , ⁵⁴ ]). Thus, each HLA-C allotype is recognized by KIR2DL1 or by KIR2DL2/3. Interestingly, the amino acid at p44 of the protein sequence of a KIR determines its specificity for a given HLA-C group: If it is methionine (as in the case of KIR2DL1), the KIR binds group II HLA-C, and if it is lysine (as in the case of KIR2DL2/3), the KIR binds group I HLA-C [⁵⁶ ]. It may be relevant to mention here that these ligand specificities are not absolute: KIR2DL1 and KR2DL2/3 may bind to group I and group II HLA-C ligands, respectively. However, they do so with tenfold lower affinities.

KIR2DL4 (CD158d) is unusual in several respects. First, it binds HLA-G: a nonclassical HLA antigen. Second, it is expressed mainly in endocytic vesicles and binds internalized, soluble HLA-G. Third, the receptor is expressed usually by all human NK cells. Its expression can also be increased by cytokines, e.g., IL-2. Fourthly, the receptor has an ITIM-containing, long cytoplasmic tail (a typical feature of an inhibitory KIR) as well as a charged amino acid (arginine) in its transmembrane region (a feature of an activating KIR). The presence of a charged amino acid in its transmembrane region allows it to associate noncovalently with the signaling adaptor molecule chain of the FcRI. Cross-linking of the receptor with HLA-G-expressing target cells induces secretion of IFN- from NK cells but does not trigger cytotoxicity [^{59 60 61 62 63 64} ]. It is noteworthy that HLA-G is expressed in the female reproductive tract, invading placental trophoblasts and thymic epithelial cells. The HLA-G/KIR2DL4 interactions may be important in generating local immune responses against invading pathogens in the female reproductive tract. Uterine NK cells express KIR2DL4, and secretion of IFN- from uterine NK cells has been shown to be crucial for vascularization of placenta (reviewed in ref. [⁶⁵ ]). KIR2DL4 is expressed at lower levels on uterine NK cells in women undergoing spontaneous, recurrent abortions [³² ]. Gomez-Lozano et al. [⁶⁶ ] have described a multiparous woman lacking KIR2DL4 in her genome. It is probable that a KIR2DL4-like receptor may have compensated the function of this receptor in this woman.

The KIR2DL5A and KIR2DL5B were considered as allelic forms of the same gene. However, now, it has become quite obvious that they represent two closely related but distinct genes, which are present in telomeric and centromeric halves of the KIR gene cluster, respectively [⁶⁷ ]. The KIR haplotypes may have both, none, or one of the two genes. In fact, the KIR genes are evolving so rapidly that our conventional ways of distinguishing between alleles and genes are being challenged. KIR2DL5A (previously known as KIR2DL5*001 allele) is expressed, like other clonally expressed KIR genes, as a monomer on CD56^low NK cells in a variegated manner. It is also expressed on a subset of T cells [⁶⁸ ]. Individuals (52–80%) may express this receptor, depending on the population group. KIR2DL5B is a hybrid gene that arose from recombination between KIR2DL5A and KIR3DP1 genes. It has three alleles, KIR2DL5B*002, *003, and *004, of which only *003 is expressed. The KIR2DL5 A and B genes have 99.58% sequence similarity in their exons. Each KI2DL5 receptor has two ITIMs, of which one is atypical. The receptor has inhibitory function and preferentially recruits SHP-2 [⁶⁹ ]. The ligand for KIR2DL5 is not known. However, their extracellular regions are similar to that of KIR2DL4. Therefore, it is believed that KIR2DL5 receptors also bind HLA-G. Interestingly, KIR2DL5 genes are conserved among primates.

Three-domain KIR and their ligands.
Of the three-domain KIR, KIR3DL1 (p70) is expressed as a monomer on the surface of NK cells. It binds to HLA-B and HLA-A allotypes bearing the HLA-Bw4 serospecificity. It is noteworthy that all HLA-B allotypes can be divided into two mutually exclusive Bw4 or Bw6 serospecificities depending on residues 77–83. About one-third of all HLA-B and some HLA-A allotypes are Bw4⁺. The remaining two-thirds of the HLA-B allotypes is Bw6⁺. It may be relevant to mention here that HLA-Bw4 allotypes also show dimorphism at p80 of their amino-acid sequence: They may have isoleucine (HLA-Bw4-I) or threonine (HLA-Bw4-T) at this position. It was demonstrated that KIR3DL1 receptors bind the former HLA-Bw4 allotypes with higher affinity [⁷⁰ , ⁷¹ ]. As mentioned above, the KIR3DL1 gene exists in 47 allelic forms, encoding 41 distinct allotypes, which differ in their ability to bind their MHC ligands. Interestingly, this binding is dependent on the peptide bound to the peptide-binding groove of the MHC class I ligand [^{72 73 74} ]. Some KIR3DL1 allotypes (*001, *002, *008, *015, *009) are expressed at relatively higher levels on the surface of NK cells, and others (*005, *007) are expressed at lower levels. Epidemiological data from Martin et al. [⁷⁵ ] suggest that the highly expressed KIR3DL1 allotypes bind HLA-Bw4-I allotypes with high affinity, as their coinheritance gives the highest protection from AIDS in HIV-infected individuals. Furthermore, it also suggests that the lowly expressed KIR3DL1 allotypes bind with HLA-Bw4-T allotypes better than with HLA-Bw4-I ones. This assumption explains the better protection provided by these KIR allotypes, when they are coinherited with HLA-Bw-T as compared with HLA-Bw4-I allotypes. However, these findings need to be tested by direct-binding assays. One KIR3DL1 allotype (*004) is not expressed on the cell surface and remains intracellular. Still, it appears to be of some functional significance [^{74 75 76} ].

Although KIR3DS1 encodes an activating KIR, it segregates as an allelic variant of KIR3DL1. To date, 12 allelic variants have been described, which encode 10 distinct allotypes of KIR3DS1. It is noteworthy that KIR3DS1 and KIR3DL1 show more than 95% sequence homology in their extracellular domains. Genetic epidemiological data strongly suggest HLA-Bw4-I allotypes as ligands for KIR3DS1 [⁷⁷ ]. Nevertheless, KIR3DS1 failed to bind HLA-Bw4 tetramers as well as HLA-Bw4 ligands when expressed in EBV-transformed human cells [⁷⁸ ]. It is likely that the receptor binds to HLA-Bw4 ligands when the latter has bound a certain foreign peptide.

KIR3DL2 (NKAT4; p140) is expressed as homodimers on the surface of NK cells. It binds different HLA-A antigens when complexed with certain peptides derived from the viral protein EBV nuclear antigen 1 (reviewed in ref. [⁵³ ]). The ligands for other KIR are not yet known (see Table 5 ).

Affinities of KIR for their ligands.
It is important to note that KIR differ in their affinities for their MHC ligands. For example, the KIR2DL1 binds with group II HLA-C with higher affinities than does KIR2DL2 for its respective MHC ligands (group I HLA-C). Furthermore, KIR2DL2 has higher affinity for its ligands than its allelic variant KIR2DL3. Similarly different KIR3DL1 allotypes bind to HLA-Bw4 allotypes with different affinities. These differences in affinities of different KIR for their respective MHC ligands are important from the functional point of view as they translate into different levels of inhibition of the NK cells. The differences in affinities are more pronounced between activating and inhibitory KIR.

The S KIR have activating functions. They may represent an allelic variant of an inhibitory KIR gene (e.g., KIR3DS1 is an allelic form of the KIR3DL1) or may represent a distinct activating KIR gene (e.g., KIR2DS4). It is believed that activating KIR bind the same HLA antigens as do their inhibitory counterparts but with several orders of magnitude lower affinities. In fact, many authors believe that these receptors may bind some unknown ligands expressed by human pathogens, malignant cells, and/or they may bind their cognate MHC ligands that have bound foreign pathogen-derived peptides [⁵² , ⁵³ , ⁷⁹ ]. It is noteworthy that KIR2DS4 was reported to bind an unknown ligand present on the surface of melanoma cells [⁸⁰ ]. The idea is supported further by the fact that certain activating forms of LY49, which are functional homologues of KIR expressed on murine NK cells, bind certain viral proteins. For example, an activating receptor LY49H, which is present on NK cells in C57BL/6 mice, binds a murine CMV (MCMV)-encoded glycoprotein m157 and protects the host from the virus [⁸¹ ]. The virus-susceptible mouse strain 129/SvJ lacks this receptor and instead expresses an inhibitory receptor LY49I for the viral glycoprotein on NK cells. The viral glycoprotein m157 is an MHC class I homologue encoded by MCMV to evade the host’s NK cell responses [¹ ]. Another activating receptor LY49P recognizes MHC class I antigens (H-2D^K) in mice when bound with a viral peptide [⁸² ].

A functional consequence of the different affinities of the inhibitory and activating KIR for their MHC ligands is that under physiological conditions, inhibitory KIR act as dominant-negative regulators for NK cell functions. They are the main receptors that regulate NK cell functions in humans and maintain tolerance of NK cells toward one’s own cells.

KIR-binding and MHC-bound peptides.
The binding of two-domain KIR to their MHC ligands is sensitive to the nature of the bound peptide. Certain amino-acid side-chains at p7 and p8 of the peptide may interfere with the binding [⁸³ ]. Otherwise, these KIR do not distinguish between self and nonself peptides bound to their MHC ligands. However, the three-domain KIR are sensitive to the peptide bound to Bw4. Usually, they can bind to their MHC class I ligands complexed with endogenous peptides. This prevents NK cells from killing the body’s own cells. The binding of a foreign peptide to their MHC ligands may abrogate their binding with these KIR. This may result in loss of the KIR-imposed inhibition on the NK cell. For example, the binding of a neomycin-derived peptide to HLA-B27 abrogates its recognition by KIR3DL1 [⁸⁴ ]. Neomycin-expressing cells are no longer recognized by NK cells expressing this KIR and hence, may be killed. Such interference with KIR recognition may have consequences for the cell’s susceptibility to NK cell-mediated killing. In this respect, the three-domain KIR behave as TCRs as far as recognition of HLA molecules is concerned. However, the consequences of the recognition are quite opposite to each other: T cells recognize HLA via TCR and kill target cells, whereas NK cells recognize HLA via KIR3DL1 and spare them from killing. As three-domain KIR may recognize several HLA ligands in association with one or more pathogen-derived peptides, they essentially remain pattern-recognizing molecules, and TCRs recognize only a particular HLA in association with a well-defined, single foreign peptide and are antigen-specific.

CD94/NKG2C killer lectin-like receptor (KLR)-C (NKG2/CD94 family)
They are also known as the NKG2/CD94 family of receptors. The receptors of this family are type II, C-type, lectin-like integral membrane glycoproteins. As shown in Figure 4 , they are expressed on the cell surface as heterodimers with CD94 (NKp43; KLR-D1), which is also a type II, C-type, lectin-like polypeptide. CD94 lacks a cytoplasmic tail and cannot transduce signals. However, it is essential for the cell surface expression of NKG2 receptors. Members of this family as well as other non-KIR human NKR are given in Table 6 . There are four receptors in the family: A/B (KLR-C1), C (KLR-C2), E/H (KLR-C3), and F (KLR-C4). B and H represent splice variants of A and E genes, respectively [⁵² , ⁵⁴ , ⁸⁵ ]. The genes for these receptors are located on human chromosome 12p12.3–p13.2 in a region called NK gene complex (NGC). Of these receptors, CD94/NKG2A has inhibitory function, and it carries two ITIMs in its long cytoplasmic tail. It is expressed in a subset of human NK cells having the CD56^high CD16^low phenotype. It is also expressed, albeit at lower levels, on the CD56^low subset of NK cells. NKG2C has a short cytoplasmic tail, associates noncovalently with a homodimer of DAP-12, and activates NK cells upon binding with its ligands. NKG2E is also considered an activating receptor. It has a charged amino acid (lysine) in its transmembrane region, but it does not associate with DAP-12. The NKG2A and NKG2C are expressed on overlapping subsets of CD56⁺ NK cells [⁵⁴ ]. NKG2F has a truncated extracellular domain comprising only 12 amino acids. It has a charged amino acid (lysine) in the transmembrane region and two ITIMs in its cytoplasmic tail. The protein is retained intracellularly. It does not form heterodimers with CD94 but can complex with DAP-12 [⁸⁶ ]. Thus, it may sequester DAP-12 and regulate functional activities of other receptors that use DAP-12 as a signaling partner. Interestingly, DAP-12 has also been implicated in myelination and bone resorption (reviewed in ref. [⁸⁷ ]).

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Table 6. Non-KIR NKRs

The NKG2 receptors bind HLA-E: a nonclassical MHC class Ib molecule [^{88 89 90} ]. HLA-E is expressed in two isoforms in humans, and both bind equally well to these receptors. HLA-E binds a peptide, VMAPRTVLL, which is present in the signal sequences of many classical MHC class I molecules (HLA-A, -B, -C), and a nonclassical MHC class I molecule HLA-G [⁸⁹ , ⁹¹ , ⁹² ]. Without this peptide, HLA-E does not fold properly and therefore, is not expressed on the cell surface. Thus, NK cells have developed an elegant way to monitor the overall expression of MHC antigens on the surface of target cells by CD94/NKG2-mediated monitoring of HLA-E. Interestingly, human CMV (HCMV) encodes a glycoprotein UL40, which increases the expression of HLA-E on the surface of the virus-infected cells by providing this peptide and hence, increases their resistance to killing by NK cells [⁹³ ]. HLA-E is normally expressed as well as released by placental trophoblasts, vascular endothelial cells, and peripheral blood cells (monocytes, DC, and T, B, and NK cells). Its expression is increased on human cells by certain cytokines, e.g., IFN-, TNF-, and IL-1β [⁹⁴ ]. The expression of HLA-E on human cells may protect them from NKG2A-bearing NK cells, and soluble HLA-E may interfere with this protection.

The KLR family NKRs have nonclassical, lectin-like domains. Therefore, they can bind nonsugar moieties on their ligands [⁹⁵ ] (reviewed in ref. [⁹⁶ ]). It has been demonstrated in vitro that NKG2A can bind efficiently to HLA-E produced in bacteria.

ILT (CD85) family
The family has also been given other names: leukocyte Ig-like receptor (LILR) and macrophage Ig-like receptors. It comprises 13 members. They vary in the number of Ig-like domains present in their extracellular regions and may be inhibitory or activating as in the case of KIR (reviewed in refs. [⁵² , ⁵⁴ ]). They are mostly expressed on monocytes, macrophages, DC, and certain subsets of B and T cells. One member of the family ILT-2 (LILRB1; CD85j) is also expressed on a subset of NK cells (Fig. 5 and Table 6 ). The receptor has four Ig-like domains in its extracellular region and four ITIMs in its cytoplasmic tail. ILTs bind classical and nonclassical HLA molecules (e.g., HLA-G). ILT-2 preferentially binds HLA-G [⁹⁷ ]. It interacts with the 3 domain of the MHC class I molecules and competes with CD8 for binding to the MHC ligand [⁹⁸ ]. ILT genes are present on chromosome 19 close to the KIR gene cluster.

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Figure 5. Non-MHC-binding NKRs. The receptors, their ligands, and signaling partners are shown. ITSM, Immunoreceptor tyrosine-based switch motif; Col, collagens. The YxxM motif, when phosphorylated, recruits PI-3K; not drawn to the scale. The question mark (?) indicates that the ligand is unknown. NTB-A, NK-T-B (NK, T-B cell antigen) antigen; LAIR-1, leukocyte-associated Ig-like receptors.

CD160 (BY55)
It is a GPI-anchored, Ig-like molecule expressed on the CD56^dim subset of NK cells, TCR-positive T cells, and a subset of CD8⁺ T lymphocytes. It binds HLA-C, -G and other HLA molecules. NK cell stimulation via CD160 leads to secretion of a unique, proinflammatory profile of cytokines: IFN-, TNF-, and IL-6. A soluble form of the molecule, shed from activated human NK cells, can inhibit functions of CD160⁺ NK and T cells [⁹⁹ ]. CD160-positive NK and CTL are usually implicated in inflammatory conditions.

Non-MHC-binding receptors
NK cells also express several types of receptors, which recognize different molecular structures (but not MHC antigens) present on the surface of target cells. These receptors are as below.

NKG2D receptor (KLR-K1; CD314)
Originally, this receptor was placed in the CD94/NKG2 family. However, it differs from members of this family in many respects. It does not form heterodimers with CD94 (see Fig. 5 and Table 6 ). It is expressed as homodimers, and each homodimer associates noncovalently with a homodimer of an adaptor protein DAP-10, which is a DAP-12-related protein but does not contain ITAM motifs in its cytoplasmic tails [¹⁰⁰ ]. Instead, DAP-10 carries a YxxM motif, which upon phosphorylation of its tyrosine residues, can recruit the regulatory subunit p85 of PI-3K and growth-factor receptor-bound protein 2. This motif is also present in the cytoplasmic tail of the T cell costimulatory molecule CD28. However, there are important differences between CD28- and NKG2D-transduced signals. The engagement of NKG2D alone, but not of CD28, on NK as well as on T cells allows formation of an IS with target cells [¹⁰¹ ].

The NKG2D receptors do not recognize and bind HLA-E, as do all members of the CD94/NKG2 family. Instead, they bind MICA, MICB, and the HCMV ULBPs [¹⁰² ]. MIC genes are located on human chromosome 6q25 outside the MHC locus. Of the six distinct MIC genes, only MICA and MICB are transcribed. Structurally, MIC proteins resemble MHC class I heavy chain, and each has three (1, 2, and 3) domains; however, they do not bind antigenic peptides and do not complex with β-2 microglobulin. The MIC genes are highly polymorphic. At least 54 MICA and 19 MICB alleles have been described. The MIC allotypes vary in their ability to bind NKG2D (reviewed in ref. [¹⁰³ ]). For example, MICA*01 and 07 allotypes bind strongly, and MICA*016 binds NKG2D weakly. Some allotypes such as MICA*08 and *010 are defective and are not expressed on the cell surface. Thus, an individual’s capacity to mediate NKG2D-mediated killing may depend on his/her inherited MIC genes. Under physiological conditions, the expression of MICA and MICB is restricted to the basolateral surface of intestinal epithelial cells and fibroblasts. However, they can be induced de novo on different host cells by stress, transformation, and viral infections. More specifically, DNA damage response triggered by stalled DNA replication, genotoxic drugs, irradiation, and hydroxyurea induces expression of MIC and other NKG2D ligands. The response is accompanied by activation of ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR) kinases. The stimuli, which do not result in the induction of DNA damage response and activation of ATM and ATR (e.g., heat shock, hypoxia, inflammation, TNF-, or IL-8), do not induce expression of NKG2D ligands [^{104 105 106 107} ]. MIC proteins may be cleaved via matrix metalloproteinases and shed from the cell surface as soluble proteins, which bind to and down-regulate the expression of NKG2D on NK cells. Tumor cells usually shed these proteins as an immune evasion mechanism [¹⁰⁸ , ¹⁰⁹ ].

The ULBPs were first discovered by their ability to bind UL-16 of HCMV and appear to have ubiquitous expression at the mRNA level. Five distinct ULBPs (1–5) have been identified. Of these, ULBP3 and -4 do not bind UL16. Structurally, they resemble MIC proteins but lack -3 domains and could be GPI-anchored (ULBP1, -2, and -3) or have transmembrane regions (ULBP4 and -5; reviewed in refs. [¹¹⁰ , ¹¹¹ ]). In the mouse, NKG2D recognizes H-60 (a minor histocompatibility antigen), the retinoic acid early inducible protein 1 (Rae-1), and a murine ULBP-like transcript 1 (reviewed in ref. [⁹⁶ ]).

NKG2D is an activating NKR. In addition to NK cells, resting and activated human CD8⁺ T lymphocytes express NKG2D [¹¹² ]. Both of these cell types can efficiently kill NKG2D ligand-positive target cells. The CD8⁺ T cells do so without their TCR coengagement [¹¹³ ]. Certain cytokines, e.g., IL-12 and IL-15, can increase expression of NKG2D on these cytotoxic cells, whereas cytokines such as TGF-β and IL-10 can decrease their expression. The cytokine-induced, increased expression of NKG2D on CTL greatly enhances their NK cell-like killing capabilities (reviewed in ref. [¹¹¹ ]). NK cells may play an anti-inflammatory role by killing overtly activated macrophages, which start expressing ligands for NKG2D [¹⁷ ]. It is noteworthy that stimulation of macrophages via TLR induces NKG2DL in macrophages [¹¹⁴ ]. On the other hand, certain cytokines such as IL-1β and TNF- have been shown to induce MIC and ULBP expression on oligodendrocytes and neurons. NKG2D-mediated killing of oligodendrocytes has been shown to play a role in the development of multiple sclerosis in humans [¹¹⁵ ].

Natural cytotoxicity receptors (NCRs)
Three NKRs, NKp46 (CD335), NKp30 (CD337), and NKp44, are called NCRs (Table 6 and Fig. 5 ). They trigger NK cell-mediated killing and secretion of IFN- upon their engagement. NKp46 and NKp30 are expressed on resting and activated NK cells, whereas NKp44 is expressed only on cytokine-activated NK cells [^{116 117 118} ]. NCRs belong to the Ig superfamily (IgSF). They have extracellular Ig domains and associate noncovalently with DAP-12 (NKp44), - (NKp46), and - chains (NKp30). The ligands for the NCR mostly remain unknown. Two members of the group, NKp46 and NKp44, are known to bind the sialic acid-binding glycoproteins, e.g., HA and HA-neuraminidase, of the influenza and parainfluenza viruses, respectively [⁴⁰ ]. 2,6-Linked sialic acid moieties and the sugar-carrying residue Thr 225 near the membrane proximal region of the receptor play an important role in binding to the ligands [¹¹⁹ ]. The NCR ligands may also occur on normal hematopoietic cells. For example, NK cells specifically use NKp30 to kill immature DC, suggesting that these cells bear NKp30 ligands. NKp46-positive NK cells protect host from influenza viruses, as the viruses cause lethal infections in NKp46-deficient mice [¹²⁰ ].

NKR-P1 (CD161; KLR-B1)
The receptors occur as s–s-bonded homodimers on the cell surface. They were first described in mice as NKR-P1C or NK1.1 antigen occurring on NK cells of C57BL/6 mice. In rodents, five distinct genes (A, B, C, D, and F) have been described. They encode activating receptors except for B and D genes, which encode inhibitory versions of the receptor. The humans have A gene. Its protein (CD161) is expressed on NK cells, NKT cells, and a fraction of CD8⁺ T cells. The human CD161 binds LLT-1 and transmits activating signals via the -chain of the FcRI. LLT-1 is usually expressed on monocytes and T, B, and NK cells. IL-2 can induce its expression on NK cells. The receptor differentially regulates NK and T cell functions: It increases TCR-mediated IFN- production in T cells but inhibits cytotoxicity and IFN- production in NK cells [¹²¹ ]. Another study has shown that the receptor cross-linking induces IFN- production but not cytotoxicity in human NK cells [¹²² ]. Thus, the receptor may perform dual functions. The occurrence of the receptor and its ligand on NK and T cells suggests that the receptor may interact with its ligand in cis.

SLAM-related receptors (SRRs)
The SLAM (CD150) is expressed in T cells and transmits its signals via an adaptor protein called SLAM-associated protein (SAP; or SH2D1A). The SRRs include 2B4 (CD244), NTB-A (Ly108), and CD2-like receptor on activated cytoxic cells (CRACC; CD139). These receptors are related to SLAM, as they all use similar signaling molecules, SAP, or related molecules (see Table 6 ). The genes for SRR are located on human chromosome1q22. They are expressed on NK cells, monocytes, basophils, TCR-bearing T cells, and CD8⁺ T cells of the effector/memory phenotype (Fig. 5) . The receptors bear so-called ITSM (TIYxxV/I) in their cytoplasmic tails. These receptors transmit activating signals via SAP, which has a motif in its SH2 domain centered on Arg 78. This motif binds the SH3 domain of the src family kinase Fyn (reviewed in ref. [¹²³ ]). SAP-Fyn-mediated signaling is important for TH2-type cytokine responses. Interestingly, SAP KO mice lack NKT cells [¹²⁴ ]. A distal tyrosine-based motif (TVYxxV/I) in the cytoplasmic tail of the receptor can recruit SHIP, which can dephosphorylate phosphatidyl 3,4,5-triphosphate to phosphatidyl 3,4-biphosphate. Another SAP-like adaptor protein, EAT-2 or SH2D1B, can replace SAP and associates with SRRs. However, EAT-2 cannot recruit Fyn. In the absence of SAP, 2B4 may act as an inhibitory receptor. As a result of this ability of 2B4 to act as an inhibitory as well as an activating receptor, it is recognized as a receptor with dual functionality. Early in ontogeny when NK cells become cytolytic but still have not yet expressed KIR and NKG2A receptors, they do not express SAP. 2B4 acts as an inhibitory receptor and prevents autoaggression from these developing NK cells. It has been demonstrated that EAT-2 and SAP bind 2B4 in resting and activated NK cells, respectively. The ligand for 2B4 is CD48, which is widely expressed on human cells except plasmacytoid DC. Interestingly, 2B4 in mice mainly acts as an inhibitory receptor. 2B4 KO mice show increased cytotoxicity against CD48-expressing target cells. The mouse NK cells also express a EAT-2-related transducer, which like EAT-2, cannot recruit Fyn. The gene for SAP is located on the X chromosome in humans. It is noteworthy that genetic defects in SAP can cause X-linked lymphoproliferative disease and fatal EBV infections in humans [¹²⁵ , ¹²⁶ ]. NTB-A, like 2B4, may bind SAP and EAT-2. The two adapters seem to control cytokine production and cytotoxicity in NK cells, respectively [¹²⁷ ]. In resting NK cells, CRACC binds EAT-2 but dissociates from it upon activation and recruits PI-3K and PLC-. NK cells may interact with macrophages, CTL, and other cells via 2B4/CD48 interactions.

KLR-G1 or mast cell function-associated antigen
It is a type II lectin-like inhibitory receptor expressed as an s–s-bonded dimer on the surface of mast cells. It is also expressed on antigen-specific CTL of the effector/memory phenotype, a subset of CD56^dim NK cells, and certain CD4⁺ T cells in humans as well as in mice [¹²⁸ ]. Its cross-linking inhibits cytokine secretion and cytotoxicity but not proliferation. It inhibits IgE-mediated activation of mast cells. The receptors bind ubiquitously expressed endothelial (E), neural, and retinal cadherins or junction proteins [¹²⁹ ]. Interestingly, E-cadherins are lost in epithelial tumors undergoing metastasis.

FcRL
They make a growing family of molecules with homology to FcRI. All FcRL are mainly expressed on B cells; however, one member of the family, FcRL6, is expressed on the surface of NK cells as well as on a subset of CD8⁺ T cells of the effector-memory phenotypes [¹³⁰ ]. Its novel cytoplasmic, cysteine-rich motif can recruit SHP-2 and inhibit cellular functions.

NKp80 (KLR-F1)
It is a type II lectin-like molecule expressed as s–s-bonded homodimers on the surface of NK and CD3⁺CD56⁺ T cells. The cytoplasmic tail has two E/KxYxxL/T tyrosine-based motifs. It is expressed on NCR^dull and NCR^bright NK cells. The receptor binds AICL, which is a myeloid-specific activating receptor [¹³¹ ]. Its gene is located in the NGC close to that of CD69.

DNAM-1 (CD226)
The receptor belongs to the IgSF. It is expressed on the surface of NK, T, and a subset of B cells in physical association with LFA-1. Its gene is located on human chromosome 18q22.3 (Fig. 5) . Its ligands include PVR (CD155), Nectin-2 (CD112), and nectin-like molecules, which are widely expressed on a variety of cells, e.g., endothelial, epithelial, and neuronal cells and fibroblasts [¹¹³ ]. The receptor is implicated in transendothelial migration, diapedesis, costimulation, and adhesion. A receptor closely related to DNAM-1 is CD96 (TACTILE). It bears 20% homology with DNAM-1 and also binds to nectins and nectin-like molecules.

Four Ig-like B7 homologues (4IgB7H or B7H)
These receptors belong to the B7 family and are expressed on NK and T cells. They may activate or inhibit the cell. One member of the family, B7-H1 [also called programmed death (PD) ligand-1], is expressed on NK cells. Its expression is increased by certain chemokines (e.g., CXCL-9, -10, and -11) on NK cells [¹³² ]. The receptor is also expressed and/or can be induced on several cell types in the body. The receptor interacts with its ligand PD-1 and causes premature activation of naïve T cells and inhibition/apoptosis of antigen-specific effector cells. It may be relevant to mention here that increased expression of PD-1 on HIV-specific T cells has been implicated in immunodeficiency in HIV-infected persons [¹³³ ].

SIGLEC-7 [p75; adhesion receptor molecule-1; (AIRM-1); CD328]
SIGLECs are a family of sialic acid-binding Ig-like lectins, which belong to the superfamily of sialoadhesion proteins. Of these molecules, SIGLEC-7 (or AIRM-1) is expressed on the surface of human NK cells. Two other molecules, SIGLEC-9 (CD329) and SIGLEC-3 (CD33), are expressed relatively weakly on human NK cells. The SIGLECs transduce inhibitory signals upon binding with sialic acid moieties.

CEACAM-1 (CD66a)
It binds CEA and CEA-related antigens, which are expressed on tumor cells. The binding inhibits NK cell-mediated functions [¹³⁴ ]. One of its ligands is PECAM-1 (CD31), which is expressed on vacscular endothelial cells as well as on NK cells. Cross-linking CD31 on NK cells activates LFA-1 [¹³⁵ ].

LAIR
Two members of the family, LAIR-1 (CD305) and LAIR–2 (CD306), have been described [⁵² , ⁵⁴ ]. They are ubiquitously expressed on all leukocytes including NK cells. LAIR-1 has one Ig-like domain in its extracellular region and one ITIM in its cytoplasmic tail. The receptors bind collagens, which are abundantly expressed proteins in the body. Collagens are not present in blood, so leukocytes are only exposed to the LAIR ligands when they extravasate blood and enter tissues.

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
NK cells express several coreceptors, which bind to their cognate ligands on target cells and send costimulatory signals. These signals add to the overall strength of the activating signal. Adhesion molecules, which include integrins, selectins, and Ig-like molecules, usually act as coreceptors for NK cells (listed in Table 7 ). The distinction between NKRs and coreceptors is not very clear. Some molecules considered as coreceptors (e.g., LFA-1) may trigger NK cell-mediated lysis under appropriate conditions and hence, may qualify as activating receptors.

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Table 7. Human NK Cell Coreceptors

Integrins are heterodimers of and β chains and may be of β1 and β2 types. LFA-1 is a β2 integrin (_L:β2; CD11a/CD18), which is expressed by NK cells and other leukocytes. It is involved in essential early steps in NK cell-mediated killing [¹³⁶ ]. It mediates contact and adhesion of NK cells with the target cell as well as polarization of cytoskeleton (actin and microtubules) and granules in NK cells toward the target cell [⁴⁴ ]. It is noteworthy that certain chemokines and cytokines (such as CCL-5, IL-2, and IL-15) as well as inside-out signaling from certain activating receptors (such as CD31) can induce conformational changes in LFA-1. These changes enhance affinity and avidity of the integrin for its ligands. Other β2 integrins expressed by NK cells include type III complement receptor (CR3; Mac-1; _M:β2; CD11b/CD18) and CR4 (_X:β2; CD11c/CD18). The β1 integrins expressed by NK cells include VLA-4 (4β1; CD49d/CD29) and VLA-5 (5β1; CD49e/CD29). They were named so because of their late expression in the course of T cell activation. Their ligands are indicated in Table 7 . NK cells use these molecules to interact with vascular endothelial cells. These interactions are important for NK cell extravasation and also regulate angiogenesis. The costimulation of NK cells via integrins usually facilitates their cytotoxicity and cytokine secretion. However, coligation of 4:β1 has also been implicated in the inhibition of CD16-mediated killing of NK cells [¹³⁷ ].

CD56 is an isoform of the N-CAM and is involved in homotypic cell adhesions. It is an IgSF member. The expression of CD56 on the surface of CD8⁺ T lymphocytes coincides with their acquisition of cytolytic potential [¹³⁸ ]. Twenty percent to 30% human (but not murine) NK cells express CD8 on their surface. This coreceptor stabilizes interaction of NK cells with target cells by binding with MHC [⁵⁴ ]. CD69 is an early marker of NK cell activation. Its expression correlates with the cytotoxic potential of NK cells. CD25 represents the IL-2R chain. Its expression correlates with the proliferative capacity of NK cells in response to picomolar concentrations of this cytokine. CD27 is a member of the TNFR family. It binds transferin receptor (CD70) on target cells. CD44 binds hyaluronic acid on matrix proteins and facilitates LFA-1-mediated adhesion. CD59 is a GPI-anchored membrane glycoprotein, which physically interacts with NKp30 and NKp46 on the surface of NK cells. It is a complement regulatory protein and protects cells from death as a result of complement activation. It binds to the complement proteins C8a and C9. As a result of its physical association with the NCR, it transduces positive signals upon binding to its ligands and thus, acts as a coreceptor for NK cells.

Finally, resting fetal NK cells but not adult human NK cells express CD28, CD80 (B7.1), and CD86 (B7.2) as coreceptors.

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
It has been demonstrated that no activating NKR alone is able to kill insect (Drosophila) cells expressing its cognate ligands [⁴⁴ ]. The engagement of LFA-1 by its ligands expressed on insect cells causes contact and adhesion as well as polarization of NK cell granules and cytoskeleton. Nevertheless, it does not result in degranulation of NK cells. On the other hand, the engagement of CD16 by human IgG expressed on insect cells causes contact and degranulation of NK cells but not polarization of their cytoskeleton. However, a simultaneous engagement of CD16 and LFA-1 results in contact, adhesion, polarization, and degranulation of NK cells resulting in secretion of cytokines and killing of the target cells. Thus, activating signals emanating from these two distinct receptors complement each other in NK cell-mediated killing of target cells. It has been demonstrated that cross-linking of CD2, 2B4, or NKG2D alone by specific mAb results in minor Ca⁺⁺ fluxes in resting human NK cells [⁴⁴ , ¹³⁷ ]. These data suggest that there exists a certain degree of division of labor among NK cell-activating receptors. It is noteworthy that different activating receptors and coreceptos may differ from each other in their signaling pathways. Two activating receptors with disparate signaling pathways may complement each other and trigger NK cell-mediated killing. On the other hand, a simultaneous engagement of two or more receptors with similar signaling pathways (e.g., use of ITAMs) may not result in triggering NK cell funtions. They may simply show functional redundancy and not complementarity. Therefore, a combination of at least two activating receptors with disparate signaling pathways must be coengaged by target cells to provoke NK cell-mediated killing. This implies that to be killed by a NK cell, it is compulsory for the target cell to express cognate ligands for at least two distinct activating NKRs. This provides a safety mechanism against autoaggression by NK cells. The reductionist approach of analyzing functions of activating NKRs in insect cells has challenged traditional concepts of NKRs and coreceptors. In the light of these observations, a reappraisal of the role of various NKRs in the process of NK cell-mediated killing is needed.

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NK cell-mediated killing of target cells is tightly controlled by inhibitory and activating receptors. This control ensures that NK cells do not kill normal, healthy cells of the body and cause tissue destruction (autoimmunity). As mentioned above, KIR and NKG2A are the main NKRs that inhibit NK cell-mediated killing. These receptors bind MHC class I antigens. Therefore, the body’s healthy cells, which express normal levels of these self-antigens, are spared from NK cells. The existence of MHC class I antigen-specific inhibitory receptors was in fact predicted by the "missing-self hypothesis" proposed by Kärre’s group in the mid-1980s [¹³⁹ ]. These workers observed that NK cells preferentially killed tumor cells, which lacked or have reduced expression of MHC class I antigens. They also observed that MHC-positive cells were resistant to killing by NK cells (reviewed in ref. [¹³⁹ ]). Their hypothesis was based on these observations. It posited that NK cells sense the expression of MHC class I antigens on the surface of target cells and kill those cells that lack these antigens. The discovery of MHC class I-binding inhibitory receptors (e.g., KIR and LY49 on human and mouse NK cells, respectively) proved validity of their hypothesis. However, NK cells have also been found to express a multitude of activating receptors and coreceptors, which bind to various MHC and non-MHC ligands expressed on the surface of target cells. The discovery of these receptors was a surprise, as their existence was not predicted by the missing-self hypothesis.

The current model of NK cell function is based on the engagement of its inhibitory and activating receptors by their cognate ligands expressed on the surface of target cells. When an NK cell comes in contact with a target cell, inhibitory and activating receptors may bind with their cognate ligands expressed on the surface of the target cell. The balance between inhibitory and activating stimuli received by the NK cell determines whether it will kill or spare the target cell (Fig. 2) . Under physiological conditions, inhibitory signals usually remain dominant over activating ones. If for some reason, MHC class I expression is reduced on body cells, it may turn the balance of NK cell-received signals in favor of activating ones (as a result of loss of MHC-mediated inhibition of NK cells) and may make these cells susceptible to NK cell-mediated killing. Viral infections and malignancy may cause a reduction in the expression of MHC class I antigens on the surface of infected cells. That may explain, at least in part, why NK cells can kill virus-infected and cancer cells. However, it may be noted that a MHC-deficient cell is only killed if it expresses ligands for one or more activating NKRs. Furthermore, down-regulation of MHC expression by a target cell is not a prerequisite: It may become killed despite expressing normal levels of MHC antigens if it increases the expression of ligands for one or more activating receptors. Consequently, if target cells express NKG2D ligands de novo, the engagement of KIR may not be able to inhibit NK cell-mediated killing via NKG2D. If target cells express de novo NKG2D ligands and/or increase the expression of ligands for other NK cell-activating receptors as well as down-regulate the expression of MHC antigens, they would become super-susceptible to NK cell-mediated killing. The ligands for the activating NKG2D receptor may be induced on the body cells by viral infections, malignancy, or other stimuli causing genotoxic stress. Thus, NK cells sense not only the "missing or altered self" but also "induced self" to detect hazardous cells and kill them. It is noteworthy that different NK cell clones may vary in their ability to kill a given target cell. This ability depends on the repertoire of its activating and inhibitory receptors as well as its repertoire of signaling and effector molecules (perforin, FasL, etc).

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
The expression of the main NKR genes, KIR, is controlled at the transcriptional level. Once expressed, the expression remains fairly stable. KIR genes are expressed clonally on overlapping subsets of NK cells in a cumulative and stochastic manner, independently of each other. A developing NK cell keeps on expressing its KIR genes at random one after another until it has acquired an overall level of inhibition that is just sufficient to make the cell tolerant to autologous cells. An individual NK cell does not express all KIR genes present in its genome. It expresses only a subset of these genes. This mode of expression makes NK cells of an individual heterogeneous and variegated with respect to the expression of KIR (reviewed in ref. [¹⁴⁰ ]). All clonally expressed KIR genes have more or less similar upstream regulatory regions (reviewed in ref. [¹⁴¹ ]). These regions are characterized by the presence of at least two promoters: a proximal (5' to ATG codon) and a distal (located 891–1347 bases upstream of the ATG) promoter. The proximal promoter is composite and consists of overlapping and bidirectional promoters, which work in opposite directions. It can produce sense and antisense transcripts. The sense transcripts from the promoter result in splicing and expression of the KIR protein. The antisense transcripts from the proximal promoter join sense transcripts from the distal promoter, make dsRNA, and silence transcription through RNase III-type nucleases (which cleave dsRNA into small, uniform, 21 bp segments) and RNA-induced silencing kinase (reviewed in ref. [¹⁴² ]). The ratio between forward and reverse transcriptional activities of the proximal promoter of a KIR gene determines whether the gene is expressed in an NK cell. The promoter activities involve cell-specific and nonspecific transcription factors. The bidirectional proximal promoters act as probabilistic binary switches for turning on or off transcription of individual KIR genes (reviewed in refs. [¹⁴¹ , ¹⁴³ , ¹⁴⁴ ]). The direction of the transcription, once selected, remains fixed for the life of the cell. The presence of reverse transcripts for a given KIR gene from its bidirectional promoter represents lack of expression of the gene. The KIR genes, not expressed in NK cells, are maintained silent, mainly by DNA methylation of their promoter regions. The transcription start sites in KIR genes are surrounded by CpG islands, which are always methylated in nonexpressed genes. Consequently, treatment of NK cells with demethylating agents, e.g., 5-aza-2 deoxycytidine, causes expression of all silenced KIR genes. It was demonstrated that single base-pair mutations in the acute myeloid leukemia-binding sites in the promoter regions of two KIR2DL5 alleles (KIR2DL5.2 and KIR2DL5.4) result in their transcriptional silence and nonexpression as a protein [¹⁴⁵ ]. It is noteworthy that the KIR2DL4 promoter is quite different from those present in other clonally expressed KIR genes and is not controlled by probabilistic transcriptional switches. This explains why this KIR gene is expressed ubiquitously.

A consequence of the stochastic expression of KIR genes is that each NK cell of an individual has a unique repertoire of expressed KIR. On the average, three to four KIR genes (inhibitory and activating ones) are expressed in an individual NK cell [^{146 147 148} ]. At least one of these receptors binds a self-MHC class I ligand and induces tolerance to self. The KIR genotype of an individual determines the repertoire of KIR expressed on his/her NK cells. The HLA genotype of the person affects this repertoire in a subtle way. The percent of expression of a KIR on NK cells of an individual is slightly increased if he/she also expresses an HLA ligand for that KIR [¹⁴⁹ ]. A higher number of copies of an individual KIR allele also enhance its frequency of expression on NK cells. Furthermore, the number of other inhibitory KIR-HLA ligand pairs expressed in an individual also affects the expression of a given KIR on his/her NK cells; the higher the number, the lower the frequency. Therefore, it is not surprising that KIR haplotype identical sibling pairs with different MHC class I haplotypes have significant differences in the frequencies of expression of different KIR genes on their peripheral blood NK cells [¹⁵⁰ ].

KIR and NKG2/CD94 receptors are usually expressed on mutually exclusive subsets of NK cells and complement each other (Table 2) . In the course of NK cell development and differentiation, NKG2/CD94 receptors are expressed earlier. Later in development, these receptors are replaced by KIR. However, a small proportion of NK cells continues to express NKG2/CD94 receptors and does not express KIR. In blood, CD56^highCD16^low NK cells usually express NKG2/CD94 receptors.

Although an individual NK cell may express three to four KIR genes, rarely does more than one of these receptors bind to a self-MHC antigen. Consequently, each individual NK cell can sense and respond to changes in individual MHC antigens on autologous cells. It would not have to wait until there is a global decrease in the expression of all MHC antigens. A distinct advantage of the clonal and variegated pattern of expression of KIR on NK cells is that different NK cells can sense different MHC class I antigens on target cells. NK cells in an individual may express certain KIR, which may not bind to any HLA antigen expressed by him/her. The individual may not have inherited HLA ligand genes for the receptor. For example, an individual may have a KIR2DL1 gene but may lack group II HLA-C genes, which encode its ligands. This may happen, as KIR and MHC class I genes are located on two separate chromosomes (12 and 6, respectively) and are assorted independently of each other.

The expression of KIR genes on NK cells usually remains stable and is least affected by cytokines. IL-21 plays a role in the induction of these receptors on developing NK cells from CD34⁺ progenitor cells in in vitro cultures [¹⁵¹ ]. The cytokine, however, does not affect KIR gene expression in mature NK cells. In contrast to KIR, cytokines may regulate expression of other NKRs. For example, IL-15, IL-10, and TGF-β1 were shown to induce expression of CD94/NK2GA on developing NK cells as well as on the TCR-stimulated CD8⁺ T cells. TGF-β1 also reduces expression of NKp30 and NKG2D on NK cells. IL-21 increases the expression of NCR and 2B4 on NK cells. The cytokine, however, decreases expression of NKG2D on NK cells as well as on CTL. Glucocorticoids also decrease NCR expression on NK cells [^{152 153 154 155 156} ]. These studies show that changes in cytokine production, which usually accompany viral infections and malignancy, may cause changes in the expression of different receptors on NK cells as well as on T cells. An altered expression of NKR has important implications for the functional activity of NK cells; it may lead to the emergence of autoimmune NK cell clones if inhibitory receptors on NK cells are reduced, and/or activating receptors are overexpressed. NK cells may also become immunodeficient if inhibitory receptors to MHC antigens are overexpressed on them. It has been demonstrated in the mouse model in vitro and in vivo that blocking NK cell inhibitory receptors by small molecular weight inhibitors or by receptor-specific antibodies increases NK cell activity against tumors and results in their regression [¹⁵⁷ ]. The autoimmune cells may kill normal, autologous cells, whereas the immunodeficient ones may not be able to kill otherwise susceptible malignant or virus-infected cells. A dysregulated in vivo expression of KIR genes has been documented to cause immune deficiency in humans [¹²⁰ ]. The authors described the case of a person who expressed KIR2DL1 on all of his NK cells. He was immunodeficient and suffered from repeated viral and bacterial infections.

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
It was proposed that each NK cell in an individual expresses at least one inhibitory receptor (KIR or NKG2/CD94) capable of binding to a self-MHC antigen. This ensures that NK cells do not kill normal, autologous cells. However, it has been demonstrated that some NK cells may not express any inhibitory receptors (KIR or NKG2/CD94) specific to a self-MHC antigen. These cells do not kill autologous target cells and are hyporesponsive [¹⁵⁸ ]. According to one school of thought, these cells have not been "licensed" to kill and therefore, are tolerant of autologous target cells. According to the "licensing" hypothesis, NK cells must express inhibitory receptors specific for self-MHC class I antigens for acquiring killing capacity [¹⁵⁹ , ¹⁶⁰ ]. This hypothesis implies that these NK cells are somehow immature. Another group of researchers thinks that these NK cells are fully mature and capable of killing but are "disarmed" to kill autologous cells. They argue that as a result of persistent activation of these cells, their signaling pathways become attenuated [¹⁶¹ ]. The disarmed NK cells express all of the phenotypic markers of fully differentiated, mature NK cells. Upon activation with pharmacological activators, e.g., ionomycin, they can release cytokines such as mature NK cells. In conformity with the "disarming" hypothesis, NK cells from Rae-1 transgenic mice are also hyporesponsive [¹⁶² ]. Furthermore, NK cells are chronically activated in transporter associated with antigen processing 2-deficient humans but are hyporesponsive and tolerant to self. This self-tolerance could be ascribed at least partially to their reduced expression of NKG2D, -chain, and NKp46 [¹⁰ ].

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
As mentioned above, all KIR genes are tightly packed in a head-to-tail manner in the LRC region (reviewed in refs. [¹⁶³ , ¹⁶⁴ ]). Each KIR gene is 2.0 kb apart. The order of the genes in the LRC region has been deduced from sequencing of the KIR haplotypes as well from segregation analyses. KIR haplotypes vary in humans with respect to the number of activating and inhibitory genes as well as to their allelic forms. Because of these variations, a large number of KIR haplotypes have been identified. These haplotypes may be classified into two broad types: A and B. The type A haplotypes usually contain five inhibitory KIR genes. They also contain one S or activating KIR gene (KIR2DS4). This activating KIR, however, is frequently mutated and encodes a nonfunctional receptor as a result of the presence of a 22-bp deletion in exon 5 of the gene. About 80% of the Caucasians have this deletion [¹⁶⁵ ]. Therefore, type A haplotypes usually do not express a functional, activating KIR. They have an inherent tendency to strongly inhibit NK cells. Type B haplotypes are more diverse and may contain more (up to 14) KIR genes, which may include as many as five activating KIR (KIR2DS1,- 2, and -3, KIR2DS5, and KIR3DS1 but not KIR2DS4). It is noteworthy that all human KIR haplotypes contain KIR2DL4, which acts as an activating receptor despite having a long cytoplasmic tail. Figure 6 shows the prevalent KIR gene arrangements present in the most common A and B types of KIR haplotypes. Four KIR genes KIR3DL3, KIR3DP1, KIR2D4, and KIR3DL2 are present in all KIR haplotypes. Of these, KIR3DP1 is a pseudogene. These genes have been termed the "framework genes" [¹⁶³ , ¹⁶⁶ ]. The frequencies of the two haplotypes vary significantly in different human populations. For example, 60% Japanese, 30% Caucasians, and 2% Australian Aborigines are homozygous for A haplotypes [¹⁶⁶ , ¹⁶⁷ ]. It has been demonstrated that overall, 12% humans have predominantly inhibitory KIR genotypes (more inhibitory receptors than activating ones), and 36% have predominantly activating ones (more activating than inhibitory receptors). The rest (52%) have neutral KIR genotypes (equal number of activating and inhibitory KIR genotypes). Furthermore, only less than 1% of unrelated humans has the same KIR genes [¹⁶⁸ ]. In a small percentage of people, KIR may be truncated or unusually elongated. These inviduals may lack or may have duplicated copies of certain KIR genes. The KIR genotype of an individual greatly affects his/her NK cell responses to viral infections.

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Figure 6. Schematic representation of KIR haplotypes in humans. A haplotypes contain five inhibitory KIR and only one activating KIR (2DS4), which is frequently mutated. B haplotypes differ from A in having many activating KIR genes. The framework genes (3DL3, 3DP1, 2DL4, and 3DL2; in violet color) are present in each haplotype. The figure shows KIR genes present in the centromeric and telomeric halves of the frequently found A and B haplotypes above and below the framework genes, respectively. Each box in the figure represents a KIR gene. 3DP1 is a pseudogene.

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
The KIR bind specific HLA antigens and regulate NK cells functions. The two gene families are located on two different chromosomes in humans. Therefore, they segregate independently of each other in meiosis and may result in unique KIR/HLA genotype combinations in humans. These unique KIR/HLA combinations translate into unique interactions and control over NK cell functions in humans. The degree of inhibition mediated by interactions between coinherited KIR and MHC class I gene products in an individual determines the activation threshold for his/her NK cells. The differences in the inhibition of NK cells result from different affinities of different KIR for their cognate MHC ligands. Furthermore, individuals may vary in the number of KIR/MHC inhibitory pairs as well as in the number of inherited, activating KIR genes [¹⁶³ , ¹⁶⁸ ]. Apart from playing a direct role in killing virus-infected cells, NK cells effectively regulate several aspects of virus-specific, adaptive immune responses. Moreover, KIR (especially the inhibitory ones) are also expressed on virus-specific CD8⁺ T cells, and NKR/MHC interactions have been documented to control the effector function of these cells. For this reason, the effects of the KIR/MHC combinations may go beyond NK cells and determine the overall immune efficiency of the individual. For example, if a person X expresses KIR and MHC antigens that interact strongly with each other, he/she would be relatively immunodeficient as compared with person Y, whose KIR and MHC antigens interact relatively weakly with each other. From the point of view of a viral infection, the X may be at a relative disadvantage to mount an effective antiviral immune response and clear the infection as compared with the Y. However, it has also been argued that X individuals may be better than Y individuals in dealing with viral infections as a result of enhanced licensing of their NK cells for killing by high-affinity KIR [⁷⁵ ]. This argument cannot explain the experimental findings that the individuals who are homozygous for group I HLA-C and KIR2DL3 can more efficiently clear needle-prick hepatitis C virus (HCV) infections as compared with the individuals who are homozygous for KIR2DL1 and group II HLA-C [⁷⁹ ]. As mentioned above, KIR2DL1/group II HLA-C interactions are stronger and mediate tighter inhibition of NK cells as compared with that mediated by the KIR2DL3/group I HLA-C. The implications of coinherited KIR and HLA genotypes are not restricted to resistance to viral infections (reviewed in ref. [⁵¹ ]). The individuals with relatively weakly inhibited NK cells would not only better control viral infections and other intracellular pathogens, but they would also be in a better position to control malignancy. On the other hand, they may be more susceptible to the development of various autoimmune diseases. Indeed, persons suffering from type I diabetes have been reported to carry a lower frequency of inhibitory KIR/HLA gene pairs, a higher frequency of activating KIR genes, and a higher frequency of KIR2DS2/ligand gene combinations [¹⁶⁹ , ¹⁷⁰ ]. It is likely that a genetic imbalance between KIR and their ligands may have resulted in increased NK and CTL activities toward pancreatic antigens in these patients. According to this paradigm, the persons susceptible to developing autoimmune diseases may control viral infections more efficiently. Consistent with this theme, it has been reported that HIV infection progresses more slowly toward AIDS in Zambian individuals suffering from the genetically determined, autoimmune spondylarthritis as compared with the spondylarthritis-free, HIV-infected persons [¹⁷¹ ]. The frequent presence of HLA-B27 in these patients may be a contributing factor in slowing the progression to AIDS in these patients.

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Role of Bw4-binding KIR
Several genetic and functional studies have associated certain HLA allotypes with a rapid development of AIDS in HIV-infected persons. For example, the HLA-B35 Px allele has been associated with rapid progression toward AIDS, whereas HLA-B57 and HLA-B27 alleles have been associated with delayed progression. The HIV-infected persons carrying the protective alleles have slower decline of CD4⁺ T cell counts, lower viral loads in their blood (viremia), and longer AIDS-free survival. The protective HLA alleles are also over-represented in HIV-infected persons, who can control HIV replication and do not develop AIDS for long periods of time (so-called natural controllers or long-term nonprogressors). The HLA-conferred protection from AIDS has been explained on the basis of the ability of these HLA allotypes to present immunodominant viral epitopes and induce broadly reactive polyclonal antiviral CTL responses [^{172 173 174 175} ]. It is noteworthy that these protective allotypes are seropositive for the Bw4 determinant. Furthermore, Bw4/Bw4 individuals have been shown to be relatively resistant to the development of AIDS as compared with Bw6/Bw6 individuals [⁷⁵ , ¹⁷⁶ ]. As only Bw4-serospecific HLA allotypes have been shown to bind three-domain KIR, the question arises whether KIR/HLA-Bw4 interactions and NK cells could be involved in the Bw4-mediated resistance to the development of AIDS. Only a few studies have addressed this question and investigated the impact of KIR polymorphism as well as other HLA/KIR gene coinheritance on resistance to the development of AIDS. In this regard, Martin et al. [⁷⁷ ] conducted investigations in a cohort of more than 1000 North American HIV-infected persons. They reported that an activating allele of the KIR3DL1 gene, KIR3DS1, was associated with delayed progression to AIDS in humans coinheriting the HLA-Bw4-I alleles. In the absence of KIR3DS1, HLA-Bw4-I alleles were not associated with the protection. More surprisingly, KIR3DS1 alone without its HLA ligand was associated with a relatively rapid progression of the disease. In a subsequent study, the group showed that coinherited KIR3DS1 and HLA-Bw4-I alleles protected HIV-infected persons from viral burden in early stages of the infection and from opportunistic infections in late stages. Their coinheritance, however, afforded no protection from HIV-related malignancies [¹⁷⁷ ]. As mentioned above, KIR3DL1 receptors bind the HLA-Bw4-I allotypes with higher affinity [⁷⁰ , ⁷¹ ]. Therefore, it can be argued that a high-affinity interaction between KIR3DS1 and HLA-Bw4-I allotypes may have resulted in more effective immune responses (through enhanced activation of NK cells and/or of T cells, were KIR3DS1 expressed on CTL in these patients). The problem in this interpretation is that in in vitro studies, although KIR3DL1 allotypes have been shown to bind HLA-Bw4 antigens in a peptide-dependent manner, KIR3DS1 does not bind any Bw4 allotype, even when complexed with the peptides that allow binding of KIR3DL1 allotypes [⁷⁶ , ⁷⁸ ]. Alternately, a protein of viral or cellular origin, expressed de novo on the surface of HIV-infected cells, may have acted as a ligand for KIR3DS1. It is also possible that another unknown genetic determinant, which may be in linkage disequilibrium with KIR3DS1, may have been responsible for this protection. Furthermore, reasons behind the reported association of KIR3DS1 with rapid progression of AIDS in the absence of its HLA ligand remain enigmatic. Another group of researchers could not corroborate these results in an ethnically different cohort of HIV-infected persons [¹⁷⁸ , ¹⁷⁹ ]. They found no protective effect of coinherited KIR3DS1 and HLA-Bw4-I genes on AIDS progression. Instead, they found that inheritance of two linked KIR genes (KIR2DL2 and KIR2DS2; see Fig. 6 ) posed a greater risk of developing AIDS if their ligands were also present, and the presence of the KIR2DL3 gene had a moderating effect on this risk. They also found that coinheritence of the genes for Bw6 and group II HLA-C allotypes was associated with rapid progression toward AIDS. The authors concluded that HLA and KIR affect HIV progression independently as well as synergistically. In another study on 88 HIV-infected individuals, it was shown that KIR3DL1 had a protective effect on the development of AIDS when coinherited with HLA-B*57 (an allotype with Ile at p80 [¹⁸⁰ ]). An important drawback of these studies is that they did not characterize the KIR3DS1 allele in the patients and control subjects. It is noteworthy that a mutant, nonfunctional form of KIR3DS1 (*049N) also exists [¹⁸¹ , ¹⁸² ]. However, this mutant allele is rare. Martin et al. [¹⁸¹ ] reported later that their disease association data were not affected when they adjusted them for the presence of this allele. It may be relevant to mention here that KIR3DS1-expressing NK cells as well as T cells expand in viremic, HIV-infected persons [¹⁸² ]. These data suggest strongly that KIR3DS1 expression is relevant to this infection. Further studies are needed to pinpoint its exact role.

Role of KIR3DL1 alleles
It is noteworthy that KIR3DL1 has 59 alleles, 12 of which encode the activating allotypes (KIR3DS1), and 47 encode inhibitory (KIR3DL1) allotypes. Depending on their level of expression on the cell surface, Martin et al. [⁷⁵ ] have divided the inhibitory allotypes into high expressors (KIR3DL1*001, *002, *008, *015, *009), low expressors (KIR3DL1*005, *007), and no expressor (KIR3DL1*004). The last one is retained within cells as a result of its truncated, cytoplasmic tail. They presumed that the affinities of these allotypes for their MHC ligands correlated with their expression levels. They further demonstrated that highly expressing KIR3DL1 alleles were protective when coinherited with HLA-Bw4-I alleles as compared with the low-expressing allotypes [⁷⁵ ]. This study also showed relative protection afforded by low-expressing KIR3DL1 alleles when coinherited with HLA-Bw4-T as compared with the individuals homozygous for Bw6 alleles. More surprisingly, KIR3DL1*004 also provided protection, despite the fact that this allotype is not expressed on the cell surface. This shows that even an intracellularly retained KIR3DL1 allotype may have functional significance. These results from Martin et al. [⁷⁵ ] suggest that the presence of a pair of inhibitory KIR3DL1 and its HLA ligand in HIV-infected persons affords protection from AIDS progression. Furthermore, the strength of the inhibition between the receptor-ligand pair correlates positively with the degree of protection. These results are not congruent with the paradigm that the KIR/HLA combinations that favored NK cell activation provided protection from viral infections and from the development of AIDS in HIV-infected individuals. The authors have argued that if NK cells were more strongly inhibited by KIR3DL1 receptor/ligand pairs, they would be more cytotoxic once they were relieved of their inhibition. The argument derives from the hypothesis that NK cells continue to express inhibitory KIR one after the other until they acquire sufficient inhibition to become self-tolerant. Thus, more tightly inhibited NK cells would be inherently more cytotoxic once their KIR/HLA-mediated inhibition is lost. The inhibition may be lost if the expression of HLA-Bw4 decreases on the surface of the virus-infected cells. Alternately, HLA-Bw4 may present a virus-derived peptide that may make it unrecognizable by the KIR3DL1 receptor. However, this argument cannot explain why coinheritence of KIR/HLA gene pairs, which inhibit NK cells rather loosely, or the inheritance of KIR without the genes for their HLA ligands protects humans from HIV and HCV infections [⁷⁹ , ¹⁸³ ]. The authors have put forward another argument to explain their findings: In the presence of tightly inhibited NK cells, only a virus-specific, immune response is generated, avoiding a nonspecific, overall activation of the immune system. This response is more effective in suppressing HIV replication. Weakly inhibited NK cells may lead to a generalized activation of the immune response, which may cause immune-mediated pathology. However, there is no experimental evidence to support this argument. On the contrary, enhanced NK cell activation has been shown to induce better and stronger antigen-specific immune responses [¹⁸⁴ ]. Furthermore, it does not explain results from several other studies in which relatively weakly inhibited NK cells (as a result of weak-affinity KIR/HLA interactions) have been shown to provide protection from viral infections as well as from tumors [⁵¹ , ⁷⁹ , ¹⁷⁸ ]. Even in the case of HIV infection, it has been reported that persons having weakly inhibited NK cells have reduced risk of contracting the infection. The study, conducted in African female sex workers, has shown that the inheritance of inhibitory KIR genes was protective from contracting HIV infection when the genes for their cognate MHC ligands were not coinherited. More specifically, KIR2DL2/3 heterozygotes without group I HLA-C and KIR3DL1 homozygotes without HLA-Bw4 were relatively protected [¹⁸³ ]. Furthermore, it has also been reported that the persons with KIR genotypes having more activating KIR genes were also relatively protected [¹⁸³ , ¹⁸⁵ ]. In the case of i.v. drug users, stronger NK cell activities as well as a predominantly activating KIR repertoire (high KIR3DS1/KIR3DL1, NKG2C/NKG2A ratios, low expression of KIR3DL1, coinheritance of weakly inhibiting KIR/MHC pairs, i.e., KIR2DL3/HLA-C of group I) also protect from contracting HIV infection [¹⁸⁵ , ¹⁸⁶ ]. Taken together, these studies suggest that weakly inhibited NK cells not only may slow progression of HIV infection toward AIDS but also may protect from contracting HIV infection. It is noteworthy that a hierarchy of KIR3DL1 allotypes for HLA-Bw4 binding has been described [¹⁴⁹ ] that differs significantly from the one used by Martin et al. [⁷⁵ ].

Concerning the impact of KIR3DS1 and its HLA ligands, Barbour et al. [¹⁸⁷ ] have shown that the two genes affect AIDS progression independently from each other. The researchers analyzed viral load, CD4⁺ T cell counts, and KIR3DS1 and HLA-Bw4 genotypes of a cohort of 255 treatment-naïve, HIV-infected persons during the first 2 years of infection. They found that the KIR3DS1 and HLA-Bw4-I genes had distinct but independent effects on CD4⁺ T cell counts and viral loads, respectively. They noted that KIR3DS1-positive, HIV-infected persons maintained CD4⁺ T cells counts at higher levels as compared with the KIR3DS1-negative persons, irrespective of coinheritence of any Bw4-I alleles. The persons possessing HLA-Bw4-I alleles maintained lower viral loads all along the 2 years of the study period, irrespective of their KIR3DS1 status. In the persons having the receptor and the ligand genes, the effects on CD4⁺ T cell counts and viral load were simply additive and not synergistic. This study suggests a direct relationship between KIR3DS1 expression and CD4⁺ T cell counts in HIV-infected persons. It may be interesting to investigate potential interactions between KIR3DS1-positive NK cells and CD4⁺ T cells in humans. More recently, a direct role for an activating KIR, KIR3DS1, has been demonstrated in controlling HIV replication. In in vitro studies, KIR3DS1-positive NK cells inhibited HIV replication in HLA-Bw4-I-positive cell cultures in a contact and dose-dependent manner. The inhibition was significantly more as compared with KIR3DS1-negative NK cells [¹⁸⁸ ]. Collectively, these studies do suggest a role of activated NK cells in controlling HIV infection. The caveat is that uncontrolled activation may contribute to immunopathogenesis.

It is noteworthy that HIV infections in humans have arisen relatively recently. The pathogen and its host have not had sufficient time to coevolve and eliminate deleterious genes from each other. Nevertheless, KIR and MHC antigens have evolved in humans under pressure from infectious agents, malignancy, and autoimmunity over millenia. Therefore, the impact of KIR genes, especially in combination with coinherited HLA genes on the susceptibility to HIV infection and development of AIDS in human populations, should be forthcoming. The studies conducted so far have yielded discordant results. The reasons for these discordant results may include variations in the pathogenicity of HIV viruses, treatment regimens, sample sizes, variable frequency of different genes in human populations, improper statistical models, etc. A part of the problem in formulating a uniform hypothesis regarding the impact of HLA/KIR interactions on the AIDS pathogenesis is the heterogeneous nature of the KIR with respect to their dependence on MHC-bound peptides. The two-domain KIR bind HLA-C and are affected by certain amino-acid side-chains at p7 and p8 of the MHC-bound nonamer peptides [⁸³ ]. The three-domain KIR bind HLA-A and -B and are relatively more discriminating between the peptides bound to their MHC ligand Bw4. Their recognition may have implications for antiviral CTL responses. For example, if an individual has HLA-Bw4 alleles, he/she will be expressing KIR3DL1 on a subset of his/her NK cells, which will recognize HLA-Bw4 complexed with endogenous self-peptides and will be tolerant to them. If the individual becomes infected, his/her cells may bind a foreign (antigenic) peptide to its HLA. If the new peptide-bound HLA is recognized by KIR3DL1, the cell still will be protected from NK cells but may be killed by antiviral CTL. If the new HLA-peptide complex is not recognized by KIR3DL1, the cell will no longer be protected from KIR3DL1-positive NK cells. The HLA-peptide complex may, however, be recognized by the CTL, and the infected cell will also be killed by the CTL. Thus, NK cells and CTL will eliminate the infected cell. Thus, the person coinheriting KIR3DL1 and HLA-Bw4 may be better equipped to eliminate HIV-infected cells compared with the person who is homozygous for HLA-Bw6. It is noteworthy that KIR and TCR bind their cognate MHC ligands with much different kinetics and thermodynamic properties [¹⁸⁹ , ¹⁹⁰ ]. Therefore, if CTL and the KIR3DL1-positive NK cell recognize and bind the same Bw4-peptide complex, CTL may preclude the NK cell binding to the complex.

No KIR has been described that could bind HLA-Bw6 allotypes. Individuals bearing this HLA may be killed only by antiviral CTL (in the context of HLA-Bw6). It may explain why HLA-Bw4 and KIR3DL1 have synergistic effects in slowing down the progression of HIV toward AIDS (Fig. 7 ). As HLA-Bw4 homozygous persons are not likely to lack KIR3DL1, this may also explain why HLA-Bw4 homozygous individuals are relatively resistant to the development of AIDS as compared with HLA-Bw6 homozygous ones [⁷⁵ , ¹⁷⁶ ]. Furthermore, more protection may be afforded by high-affinity KIR3DL1 allotypes, as they may be more sensitive to the peptide requirements and therefore, may be less likely to recognize the HLA ligand if bound to a foreign peptide. However, at this point, it remains a speculation and needs to be proved by experimental data.

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Figure 7. NK cells with three-domain KIR behave like CTL in killing HIV-infected cells. (A) KIR3DL1 on NK cells recognize HLA-Bw4 with a self-peptide and are inhibited from killing normal, autologous cells. CTL do not recognize the self-peptide bound to the HLA and also do not kill the cell. (B) The virus-infected cell presents a virus-derived foreign peptide bound to HLA-Bw4. KIR3DL1 on the NK cell may not recognize the HLA with foreign peptide and is not inhibited from killing. The CTL may recognize the viral peptide bound to HLA-Bw4 and kill the infected cells. So, HIV-infected cells are more likely to be killed (from CTL as well as from NK cells). (C) KIR3DS1 expressed on NK cells does not bind to HLA-Bw4-I complexed with a self-peptide. CTL also do not recognize self-endogenous peptides and therefore, would not kill the healthy autologous cells. (D) A virus-infected cell presents a virus-derived foreign peptide bound to HLA-Bw4. It may be recognized by KIR3DS1 and be killed by KIR3DS1-positive NK cells. The CTL may also recognize the foreign peptide bound to HLA-Bw4 and therefore, will also kill the infected cell. Thus virus-infected, HLA-Bw4-positive cells are more likely to be killed (by virus-specific CTL and NK cells).

KIR3DS1 may be protective, as in normal uninfected persons, this receptor does not recognize autologous cells; otherwise, host NK cells may kill these autologous cells and would cause autoimmunity. In HIV-infected persons, a viral peptide may bind HLA-Bw4 and make it recognizable by the KIR3DS1. Under these conditions, KIR3DS1-positive NK cells will cause killing of the infected cell. Although KIR3DS1 and KIR3DL1 allotypes have more than 95% sequence identity at the amino-acid level in their ligand-binding, extracellular regions, they may still differ from each other in their three-dimentional structures. That is why a mAb DX9 binds KIR3DL1 but not KIR3DS1 [¹⁹¹ ]. Thus, it may not be surprising if KIR3DS1 and KIR3DL1 bind HLA-Bw4/peptide complexes.

One should not overlook the fact that KIR are also expressed on T cells, especially on the memory/effector phenotype. This is an area that needs to be addressed in HIV immunology. Furthermore, one should also keep in mind that Nef may be attenuating the protective effects of KIR3DL1/Bw4 interactions by down-regulating the expression of these MHC antigens.

Role of HLA-G-binding KIR
As stated above, nonclassical MHC class I antigens, HLA-G and -E, also act as ligands for some NKRs. HLA-G binds KIR2DL4, ILT-2, and possibly KIR2DL5. The gene for HLA-G shows limited polymorphism. It was demonstrated that an HLA-G allele, HLA-G*0105N, which codes for a nonfunctional mutant HLA-G, provides protection from HIV infection in East African female sex workers. On the other hand, inheritance of functionally active HLA-G alleles increased the risk of the infection in these workers [¹⁹² ]. It is noteworthy that HLA-G is expressed in the mucosal tissues of the female genital tract and may play a role in regulating local antiviral immunity. The authors interpreted the data by concluding that the mutant antigen protected women, as it could not inhibit their NK cells in the reproductive tract of the HIV-exposed women. Of the NKRs, which could bind HLA-G, KIR2DL4 is expressed on all CD56⁺ NK cells present in tissues in humans. However, as mentioned above in the KIR section, this receptor is not an authentic inhibitory KIR: It induces secretion of IFN- but does not trigger cytotoxicity upon binding with its ligand [⁶⁰ , ⁶³ , ⁶⁴ ]. Two other receptors, ILT-2 and possibly KIR2DL5, may also bind and inhibit NK cell functions. However, they are only expressed on a minor subset of NK cells. Notably, monocytes, macrophages, and DC abundantly express different ILT, including ILT-2, which preferentially bind and are inhibited by HLA-G [⁹⁷ ]. Thus, in the persons having mutant HLA-G, activated monocytes, macrophages, and DC may play a greater role than NK cells. It has also been reported that the African women having a mutant HLA-E allele (HLA-E*0103-G or HLA-E^G) have four times less risk of contracting HIV infection as compared with the women with wild-type HLA-E [¹⁹³ ]. It is noteworthy that the mutant HLA-E allele is expressed at lower levels and has decreased affinity for CD94/NKG2A receptors. It has also been shown that the sex worker women with HLA-E and HLA-G mutant genotypes (homozygous for HLA-E^G as well as heterozygous for HLA-G*0105N) had more than 12-fold decreased risk of contracting HIV infection [¹⁹³ ]. These results implied a synergistic interaction between mutant HLA-E and HLA-G alleles in affording protection from HIV infection. These studies also suggest that blocking HLA-G and HLA-E interactions with NKR may enhance innate resistance to HIV.

Taken together, it can be postulated that coinheritance of genes for any NKR/ligand pair that weakens NK cell inhibition in the body and decreases activation threshold of NK and T cells is likely to provide protection from HIV and other viral infections. In this respect, the three-domain KIR behave as TCRs in recognizing MHC-bound peptides. If they fail to recognize the MHC-bound foreign peptide, they release the NK cell from inhibition. The NK cell will kill the virus-infected cell and so will do the virus-specific CTL. These two effector cells will be more effective in controlling HIV infection and delaying onset of AIDS in the persons who coinherit KIR3DL1/HLA-Bw4 genes. If the three-domain KIR also recognize the foreign peptide, then the NK cell will be inhibited from killing the target cell. These results have implication for HIV vaccine strategies. Viral peptides, which are recognized by CTL, but not by KIR3DL1, may serve as better immunogens. They may arouse NK and CTL responses for killing the infected cells.

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
Advances made in understanding NK cell immunobiology have enabled us to appreciate the role of NK cells in host resistance to these infections. The functional activities of these cells are controlled by a multitude of inhibiting and activating receptors and coreceptors. Of these receptors, the genes encoding KIR and their HLA ligands are highly polymorphic. Therefore, it is not surprising that coinheritance of these genes and their epistatic interactions is important in determining the status of NK cell activation, overall immune reactivity, and innate genetic resistance of humans to viral infections, malignancy, and autoimmune diseases. Researchers have just begun unraveling the role of these interactions in these diseases.

In the case of HIV infection and AIDS, few studies conducted so far highlight the significance of HLA and KIR genes as well as of their interactions in determining our innate susceptibility to the infection and its progression to AIDS. Many of these studies lacked adequate sample sizes and did not take into account allelic variations. For example, all major KIR genes have allelic variants that encode nonfunctional receptors. Furthermore, different allotypes of a given KIR differ widely in their affinities for MHC ligands. Future studies should take into account the impact of these variants on the susceptibility/resistance of humans to the infection as well as on the rate of progression toward AIDS. The results could have a profound impact on our understanding of the role of NK cells in controlling HIV infection. In view of the large number of KIR genes, their alleles, differences in gene doses, and lack of knowledge about the ligands for activating KIR, the task of investigating the impact of KIR/HLA interactions on HIV infection is challenging but worth undertaking. The results would have enormous implications for the immunotherapy, prognosis, and vaccination of HIV infections. Such studies would require larger sample sizes, accurate clinical data, and proper stratification of study participants with respect to their ethnic backgrounds. Furthermore, the researchers must use models that include all KIR alleles and their ligand genes as well as all other known genetic determinants that affect host resistance to HIV infection.

In determining the role of genes for NKRs and those of their ligands, researchers have ignored the potential involvement of the ligands for KLR-D (NKG2D) receptors, i.e., MICA and MICB proteins, which exist in more than 50 and 20 allotypes, respectively. These allotypes vary in their affinity for NKG2D. The nature of the allotype(s) carried by an individual could greatly affect his/her NK cell ability to kill target cells. They have been shown to play a role in autoimmune diseases such as celiac disease, diabetes, etc.

Finally, research in this field is seriously hampered by lack of appropriate mAb to identify individual NKR genes and their allelic variants. Development of such reagents should be a priority. This would allow determining the level of expression of the genes at the protein level and supplement genetic data with more relevant protein data. Furthermore, these antibodies could serve as important tools for manipulating receptor/ligand interactions for therapeutic purposes.

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 
A recent publication showed significantly enhanced frequency of KIR3DS1 homozygotes but not of the combination of the KIR3D gene with HLA-Bw4 or HLA-Bw4-I genes in HIV-exposed uninfected individuals compared to HIV-infected ones [¹⁹⁴ ].

 
We thank our colleagues at the Research Center for insightful discussions, the Canadian Institutes of Health Research (CIHR), and Fonds de recherche en santé du Quebec (FRSQ) for support. A. I. holds a Ph.D. scholarship from the FRSQ. We regret that as a result of space limitations, all authors on the subject could not be cited.

Received September 24, 2007; revised February 25, 2008; accepted February 26, 2008.

TOP ABSTRACT INTRODUCTION NK CELLS NK CELL FUNCTIONS NK CELL ACTIVATION REARRANGEMENT OF CYTOSKELETON IN... NKRs NK CELL CORECEPTORS DIVISION OF LABOR AMONG... REGULATION OF NK CELL... EXPRESSION OF NKRs ROLE OF INHIBITORY RECEPTORS... KIR HAPLOTYPES KIR-HLA EPISTATIC INTERACTIONS... KIR-HLA INTERACTIONS IN... PERSPECTIVE AND FUTURE... NOTE ADDED IN PROOF REFERENCES

 

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