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(Journal of Leukocyte Biology. 2003;74:16-24.)
© 2003 by Society for Leukocyte Biology

G protein-coupled receptors in natural killer cells

Azzam A. Maghazachi

Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Norway

Correspondence: Azzam A. Maghazachi, Department of Anatomy, University of Oslo, POB 1105, Blindern N-0317, Oslo, Norway. E-mail: azzam.maghazachi{at}basalmed.uio.no


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ABSTRACT
 
Natural killer (NK) cells are capable of killing tumor as well as virally infected cells. How these cells migrate toward the infected sites in the body is not completely understood. Chemokine receptors that belong to the heptahelical family of receptors and characteristically bind heterotrimeric G proteins are present in most NK cells. Recent results showed that resting NK cells highly express constitutive chemokine receptors (CCR4, CCR7, CXCR4, and CX3CR1) with low expression of a limited repertoire of inflammatory chemokine receptors (CCR1 and CXCR3). However, only a subset of these cells expressing the CD56dim and adhesion moleculehigh phenotype is capable of in vivo binding to vascular endothelium. Under pathological conditions where inflammatory cytokines are present, these cells are induced to express inflammatory chemokine receptors. Resting as well as activated NK cells also express receptors for another member of the heptahelical family of receptors that bind phosphorylated or glycosylated lysolipids. These include sphingosine 1-phosphate (S1P)1, S1P4, and S1P5, the receptors for S1P; lysophosphatidic acid (LPA)1, LPA2, and LPA3, the receptors for LPA; and T cell death-associated gene 8, the receptor for psychosine. Similar to chemokines, S1P, LPA, and psychosine induce the chemotaxis of NK cells through heterotrimeric G proteins. However, in contrast to chemokines, which enhance the cytotoxicity of NK cells, lysolipids inhibit this function. We hope that gaining knowledge regarding the distribution of activated NK cells toward the sites of tumor growth or virally infected sites will give an advantage in designing strategies using these cells as tools for the prevention and treatment of immunodeficiencies.

Key Words: chemokines • lysolipids • cancer • chemotaxis • inflammation


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INTRODUCTION
 
Natural killer (NK) cells were discovered because of the ability of a small population of blood lymphocytes to kill tumor cells [1 ]. Although it was difficult to isolate highly purified NK cells based on the technologies available, purified cells were generated by adherence to plastic flasks after 1-2 days of activation with interleukin (IL)-2 and were designated as adherent NK (AD-NK) cells [2 , 3 ]. Because of their potential application in the treatment of cancer patients, we examined the tissue distribution of rodent AD-NK cells and reported that these cells have restricted in vivo tissue localization, distributing mainly into the liver and spleen [4 ]. Also, another subpopulation of killer cells was recovered from cells cultured with IL-2, which did not adhere to plastic flasks and hence, were designated as nonadherent (NA)-NK cells. Upon examining their cytolytic behavior, the NA cells showed lower NK cell activity than the AD cells [2 , 5 ]. Although AD cells have been used for the treatment of cancers in preclinical models [6 , 7 ], it is not clear why these cells migrate toward the sites of tumor growth, and other NK cell preparations such as NA or resting NK cells do not [8 , 9 ]. Vujanovic et al. [10 ] showed that AD cells are enriched with CD56dim CD16dim or negative, as well as highly expressing adhesion molecules such as intercellular adhesion molecule, CD2, and lymphocyte function-associated antigen-1. In contrast, NA cells are CD56bright and are low in adhesion molecule expression. These observations fit well with the recent classification of human NK cell subsets into CD56dim cells representing the majority of NK cells, which is highly cytolytic, whereas CD56bright cells are low in cytotoxicity [11 ]. In addition to cytotoxicity, these subpopulations differ in their proliferative potential in response to IL-2, adhesion molecule expression, and NK receptor expression. Cooper et al. [12 ] demonstrated that CD56bright and not CD56dim cells are the primary NK cells secreting cytokines in response to monokine stimulation. Therefore, it can be suggested that CD56bright NK cells are immunoregulatory, whereas CD56dim NK cells are cytolytic.


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NK CELL RECEPTORS
 
The major functions of NK cells are tumor rejection and inhibition of virally infected cells [13 ] but usually spare normal cells from killing. Thereby, NK cells do not lyse target cells expressing certain self-major histocompatibility complex (MHC) molecules, and in fact, they are inhibited upon engaging NK cell inhibitory receptors by self-MHC molecules [14 15 16 17 ]. In addition, NK cells express stimulatory receptors by which they recognize and kill tumor target cells as well as virally infected cells [14 15 16 ]. The nature of the stimulatory receptors and their ligands on diseased target cells is beginning to be resolved [15 ]. NK cells are blood-borne and primarily found in the blood circulation and in the spleens; nonetheless, these cells migrate toward inflammatory or tumor growth sites to lyse infected cells or metastatic lesions. To facilitate their distribution into these sites, NK cells express receptors for various chemoattractants. Earlier work showed that NK cells migrate toward the concentration gradients of C5a, casein, or formyl-Met-Leu-Phe [18 , 19 ]. Although highly important and informative, these studies did not examine the nature of receptors expressed in NK cells, which facilitate their chemotaxis toward these chemoattractants.


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CHEMOKINES
 
Chemokines are low molecular weight molecules, which are divided into four subfamilies: CXC or {alpha}, CC or ß, C or {gamma}, and CX3C or {delta} [20 , 21 ]. Also several chemokine receptors—CXCR1-CXCR6, CCR1–CCR10, XCR1, and CX3CR1—have been cloned. In addition, chemokines and their receptors are classified based on their functions. Those that are up-regulated during inflammation and under pathological conditions are known as inflammatory chemokines or inflammatory chemokine receptors, whereas those that perform housekeeping functions and are involved in the circulation and homing of cells under physiological conditions are known as constitutive chemokines or constitutive chemokine receptors [22 , 23 ]. This article will review the expression and function of chemokines and chemokine receptors in NK cells (Table 1 ). Recent work showed that NKT cells also express chemokine receptors, which seem to be different from those expressed in NK cells. NKT cells will not be described in this article, but the reader is referred to recent articles examining this cell type [24 , 25 ].


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  		Table 1. Expression of Receptors for Chemokines in Human NK Cells


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ROLE OF CHEMOKINES AND CHEMOKINE RECEPTORS IN HUMAN NK CELLS
 
The first report that examined the effect of chemokines on human NK cells showed that IL-8, a CXC chemokine, induces the random motility of AD-NK cells [26 ]. Also, pertussis toxin (PTX), an inhibitor of the heterotrimeric Gi/o protein (Gi/o), inhibits IL-8-induced motility, and IL-8 activates G proteins in NK cell membranes [26 ]. These findings coincided with the cloning of the IL-8 receptors, which have been shown to be composed of seven helices that traverse the plasma membranes and belong to the seven transmembrane-spanning domain (or heptahelical) receptors [27 , 28 ]. Heptahelical receptors are members of a large family of receptors, which characteristically bind heterotrimeric G proteins within the plane of the plasma membranes and hence, are designated as G protein-coupled receptors "GPCR" [29 ]. The terms heptahelical and GPCR will be used interchangeably throughout this review. Subsequent cloning of other chemokine receptors showed that all these receptors belong to this family of receptors that signal through heterotrimeric G proteins [30 , 31 ]. In addition, members of the CC chemokines, MIP-1{alpha}, RANTES, and MCP-1, are found to chemoattract NK cells [32 ]. At the same time, Allavena et al. [33 ] reported that MCP-1, MCP-2, and MCP-3 are chemoattractants for activated NK cells. This was followed in 1995 and 1996 by other reports confirming and extending these findings [34 , 35 ]. Other CC chemokines, such as MIP-3{alpha}, MIP-3ß, MDC, TARC, or I-309; the CXC chemokines IP-10 or SDF-1{alpha}; the C chemokine lymphotactin; and the CX3C chemokine fractalkine (FKN), are all found to recruit human NK cells in vitro (reviewed in refs. [36 37 38 ]). Importantly, the chemotactic activity of these chemokines is inhibited by PTX, suggesting that this action is mediated by heptahelical chemokine receptors.

The expression of receptors for CXC chemokines (i.e., CXCR1–CXCR5), CC chemokines (i.e., CCR1–CCR8), and CX3C chemokines (i.e., CX3CR1) in human NK cells has been described (Table 1) . It appears that none of the NK cell preparations expresses CXCR2, CXCR5, or CCR5. Importantly, resting NK cells express receptors for the constitutive chemokine receptors CXCR4, CCR4, and CCR7, as determined by reverse transcriptase-polymerase chain reaction and flow cytometric analyses [39 ]. There is a low expression of the inflammatory chemokine receptors CXCR3 (~5%) and CCR1 (detected at the transcriptional level only) in resting NK cells [39 ]. The expression of CX3CR1 is contentious, as it is reported in activated NK cells [39 , 40 ] or in resting NK cells [41 , 42 ]. Equally contentious is the ligand for CCR4: Earlier findings indicate that this receptor binds RANTES and MIP-1{alpha} [43 ]; however, later work by Imai and coworkers showed that this receptor binds TARC [44 ] or MDC [45 ] but not RANTES or MIP-1{alpha}. NK cells respond chemotactically to MIP-1{alpha}, the ligand for CCR1 and CCR5 [32 , 34 ]; MDC, the ligand for CCR4 [46 , 47 ]; SDF-1{alpha}, the ligand for CXCR4 [48 , 49 ]; MIP-3ß, the ligand for CCR7 [50 , 51 ]; or IP-10, the ligand for CXCR3 [34 , 52 ], supporting the findings that chemokine receptors are expressed in NK cells. Except for CXCR4, which is down-regulated upon activation of NK cells with IL-2, the expression of the constitutive chemokine receptors CCR4 and CCR7 did not change [39 ]. This is opposite to what occurs in T cells that switch from using constitutive to inflammatory chemokine receptors upon activation [53 ]. However, similar to T cells there is increased expression of the inflammatory chemokine receptors CXCR1, CXCR3, CCR1, CCR2, CCR3, CCR6, CCR8, as well as CX3CR1 in NK cells upon activation (Table 1) . Therefore, activated NK cells may use constitutive and inflammatory chemokine receptors to extravasate into sites of infection.


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ROLE OF CHEMOKINES IN MICE NK CELLS
 
In vivo work showed that MIP-1{alpha} recruits NK cells toward the livers of cytomegalovirus (CMV)-infected mice, which resulted in increased inflammation and decreased susceptibility to infection with this virus [54 ]. The administration of lymphotactin into the peritoneal cavity of mice resulted in the accumulation of a large number of NK cells [55 ]. In CCR1 knockout mice, it was observed that NK cells do not accumulate at granulomatous lesions, which resulted in IFN-{gamma} production deficiency [56 ]. Braun et al. [57 ] showed that a murine breast cancer cell line expressing MIP-3ß is rejected by the host as a result of the secretion of this chemokine, which attracts NK cells toward the sites of breast cancer growth. A similar approach was used by Nokihara et al. [58 ] who observed that transfection of the MCP-1 gene in lung cancer cells results in the recruitment and activation of CD56+ NK cells, corroborated with decreased survival of the lung cancer cells. Taken together, the evidence is overwhelming regarding the chemoattraction effects of chemokines for NK cells in humans and in mice.


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REGULATION OF THE INFLAMMATORY CHEMOKINE RECEPTORS IN NK CELLS
 
Our model of the proposed recruitment of NK cells into the inflammatory sites is depicted in Figure 1 . In such a model, resting NK cells express mainly constitutive chemokine receptors, such as CCR4, CCR7, CXCR4, and CX3CR1, with low expression of the inflammatory chemokine receptors CCR1 and CXCR3. However, only a small subset of NK cells express adhesion molecules, and as shown by Vujanovic et al. [10 ], this subset has a tendency to adhere to plastics flasks through engaging ligands for adhesion molecules. Also, this subset binds the vascular endothelium, a process that is facilitated by adhesion molecules [60 ]. However, a strong binding to the endothelium may be induced by chemokines that are secreted by NK cells [34 , 39 , 59 , 61 ]. These chemokines may facilitate high avidity binding of NK cell adhesion molecules to their corresponding ligands present on the surface of the endothelial cells, similar to the action of chemokines in T cells [62 ]. After binding the endothelium, NK cells start to up-regulate inflammatory chemokine receptors and perhaps start to polarize, an important step that occurs just before the migration of lymphocytes [63 ]. NK cells polarize only after adhesion through integrins [59 ].



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  		Figure 1. Extravasation of NK cells into inflammatory or tumor growth sites. Several steps dictate the accumulation of NK cells at the sites of infections. (1) Initial recruitment of resting NK cells facilitated by constitutive chemokines secreted at the sites of endothelium (e.g., ELC and FKN, among others) and constitutive chemokine receptors (CCR4, CCR7, CXCR4, and CX3CR1) expressed by NK cells. (2) Adhesion of only a subset of NK cells with high expression of adhesion molecules. (3) Interaction of adhesion molecules with their ligands expressed in endothelial cells in conjunction with inflammatory cytokines (e.g., IL-2 or chemokines secreted by NK cells) will lead to shape changes and up-regulation of the inflammatory chemokine receptors (CCR8, among others). (4) Polarization of the cells, which involves the flipping of the adhesion molecules into the trailing end of the cells and the accumulation of chemokine receptors into the frontal end [59 ]. Subsequently, diapedesis and eventual recruitment of NK cells expressing a multiplicity of chemokine receptors into the inflammatory or tumor growth sites, where inflammatory chemokines are selectively secreted. CCR8+ NK cells will migrate toward tumor cells secreting I-309. However, tumor cells or virally infected cells may secrete other chemokines that selectively recruit NK cells, expressing or up-regulating receptors for these chemokines. Blue arrows indicate the sequence of the migratory events. White adhesion molecules include those that are constitutively expressed on resting NK cells. TC, Tumor cells; RAN, RANTES.

The mechanisms responsible for the up-regulation of the inflammatory chemokine receptors in NK cells are not clearly defined. One such receptor is CCR8, which is up-regulated in activated but not in resting NK cells [39 ]. Previous results showed that IL-2 alone up-regulates the expression of this receptor in NK cells [47 ]. However, perturbation of the ß2 integrins with low concentration of anti-CD11a or anti-CD18 combined with IL-2 highly up-regulates the expression of CCR8 on the surfaces of resting NK cells 7 days after stimulation (data not shown). As NK cells may enter the infected areas in the body before T cells, i.e., earlier than 7 days, it remains to be seen whether the up-regulation of CCR8 is a late event and that other receptors can be up-regulated earlier than CCR8.

Up-regulation of the inflammatory chemokine receptor CCR2 in NK cells is induced by IL-2 alone [64 ], or by IL-2 and IL-15 [59 ]. Also, CXCR3 is up-regulated in NK cells after stimulation with IL-2 [65 ] or with transforming growth factor-ß1 [39 ]. This up-regulation is corroborated with cellular responses, as these NK cells respond chemotactically toward the ligands of these receptors. The results suggest that although IL-2 is a major cytokine in this process, higher up-regulation of inflammatory chemokine receptors is achieved at the surface of the endothelial cells, where engagement of adhesion molecules takes place. In contrast to these results, Hodge et al. [66 ] observed that IL-2 and IL-12, alone and in combination, down-regulate the expression of CXCR3 in NK cells, although this was in a short-term culture, i.e., 6–24 h after incubation. Hence, depending on the time of contact between cytokines and NK cells, the expression of inflammatory chemokine receptors can vary dramatically, and hence, the response of these cells may differ significantly. Although far from being complete or clear, these studies point out the importance of the inflammatory cytokines that determine the expression of inflammatory chemokine receptors in migrating NK cells. In conclusion, a subset of NK cells, which express CD56dim and ß2integrinbright, is enriched with cytolytic activity and with cells that are capable of up-regulating inflammatory chemokine receptors and hence, can extravasate into inflamed tissues. This subset can be designated as CD56dim, ß2integrinbright, cytolytichigh, and migratinghigh.


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EXTRAVASATION OF NK CELLS INTO THE INFLAMMATORY SITES
 
Once NK cells express inflammatory chemokine receptors, they start to migrate toward the concentration gradients of chemokines secreted by tumor or inflammatory cells. There is currently overwhelming evidence showing that tumor cells selectively secrete chemokines [67 ]. In an important study, Arenberg et al. [68 ] showed that adenocarcinoma and squamous cell carcinoma of the lungs differentially secrete chemokines. For example, adenocarcinoma cells preferentially secrete MIP-1ß, whereas squamous cell carcinoma cells secrete MCP-1. Furthermore, these authors showed that although these histological types of cancer are present in the same tissue, they selectively recruit monocytes into the lungs [68 ]. These results indicate that tumor cells dictate which immune cells are recruited into the sites of tumor growth, depending on the specific chemokine secreted by tumor cells and on the appropriate chemokine receptors expressed by migrating cells. In this regard, tumor cells must select those cells that promote rather than inhibit their growth. The reasons why the anti-tumor effector NK cells are recruited into the sites of tumors are not yet clear. However, one can speculate that NK cells provide some sort of favorable environment for the growth of tumor cells by secreting cytokines such as IFN-{gamma} and IL-2 or that recruitment of NK cells may be a "bystander" effect to the chaotic and uncontrolled behavior of tumor cells.

In addition to tumors, sites infected with viruses, such as the livers of mice infected with CMV [54 ] or spleens of mice infected with vaccinia virus [69 ], are enriched with chemokines such as MIP-1{alpha} or Mig, resulting in the recruitment of NK cells toward these sites. It is clear that unless NK cells express receptors for chemoattractants, they will not migrate toward those sites in the body to perform their functions. Once NK cells establish their presence at the inflammatory sites, they start to secrete chemokines that recruit other NK cells, as well as T and dendritic cells. In HIV-infected individuals, NK cells secrete CC chemokines that inhibit M- and T-tropic HIV-1 strains [70 , 71 ]. An important aspect of the recruitment of NK cells is in allograft rejection. Hancock et al. [72 ] observed that during allograft implanting, cardiac endothelial cells secrete IP-10, which recruits CXCR3+ NK cells into the site of the allograft. Recruited NK cells secrete IFN-{gamma}, which serves to induce the production of Mig and I-TAC, leading to the recruitment of T and other host leukocytes, which facilitate the rejection of the grafts. IP-10-/- homozygotes have no or few NK cells at the sites of the cardiac allograft and consequently accept the graft [72 ].


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PHOSPHOLIPIDS
 
Recent work demonstrated that members of the phospholipids also bind heptahelical receptors. These can be classified into several family members; the most important are the lysophospholipids. Lysphophosphatidic acid (LPA) is a lysoglycerophospholipid, whereas sphingosine 1-phosphate (S1P) is a lysosphingophospholipid (Fig. 2 ). LPA is generated by the conversion of LPC by lysophospholipase D. In addition, LPA can be generated by the hydrolysis of phosphatidic acid by phospholipase A2 [73 , 74 ]. S1P is generated by the conversion of sphingomyelin into ceramide by sphingomyelinase, ceramide into sphingosine by ceramidase, and sphingosine into S1P by sphingosine kinase [75 , 76 ]. LPA and S1P are secreted by platelets and constitute a major part of serum and plasma [77 , 78 ]. S1P performs multiple biological activities and sometimes has opposite effects on the same cell types, which include neural, endothelial, hepatic, cardiovascular, as well as tumor cells [79 80 81 82 83 84 85 86 ]. Various cancer cell types secrete LPA [87 88 89 90 91 ], and LPA induces the release of angiogenic factors such as vascular endothelial growth factor [92 ]. Therefore, this phospholipid is involved in neovascularization, tumor growth, and survival. The receptors for lysophospholipids have been cloned and are found to be members of the GPCR. Those that bind S1P are known as Edg-1/S1P1, Edg-3/S1P3, Edg-5/S1P2, Edg-6/S1P4, and Edg-8/S1P5, whereas those that bind LPA are known as Edg-2/LPA1, Edg-4/LPA2, and Edg-7/LPA3, as shown in Table 2 (described in ref. [93 ]).



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  		Figure 2. Metabolism of lysolipids. These lipids are classified into glycerolipids and sphingolipids. GalTra, Galactosyl transferase; PLA2, phospholipase A2.


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  		Table 2. Expression of Receptors for Lysolipids in Human NK Cells

Recent results have shown that another phospholipid SPC, the N-deacylated derivative of sphingomyelin (Fig. 2) , binds a heterotrimeric G protein-coupled receptor known as OGR1 [94 ]. Also, another receptor was cloned in 1998, which is predominantly expressed in immature T and B lymphocytes [95 ]. This receptor is G2A and is a member of GPCR. Recent work showed that G2A binds with high affinity to the choline-containing lipid LPC [96 ]. This lipid is highly important for the induction of atherosclerosis [97 ], as it binds the oxidized, low-density lipoprotein at the artery wall. LPC is responsible for the inflammation occurring during atherosclerosis through the recruitment of monocytes and T cells into these walls. T cells secrete IFN-{gamma}, whereas macrophages produce various proteases that degrade the extracellular matrix, including interstitial collagenase, gelatinases, and stromolysin [97 ]. IFN-{gamma} secreted by T cells was found to potentiate atherosclerosis [98 ].

Psychosine (galactosylated sphingosine) is not a phosphorylated lipid but is generated by the transfer of galactose into sphingosine by galactosyl transferase [99 ], as shown in Figure 2 , or by the deacylation of galactosyl ceramide into psychosine and fatty acid [100 ]. It is increased in the brain of patients with globoid cell leukodystrophy, also known as Krabbe disease, as a result of its discoverer [101 ]. This hereditary disease affects infants who showed degenerative oligodendrocytes and progressive demyelination in the brain white matter [102 ]. Accumulation of psychosine in these patients has been attributed to the deficiency of the enzyme galactosyl ceramidase [103 ]. Importantly, this enzyme is not only deficient in the brain of globoid cell leukodystrophy patients but is also deficient in lymphocytes and fibroblasts collected from these patients [104 ]. In addition, psychosine is accumulated not only in the nervous tissues but also in the spleens, kidneys, and livers [105 ]. Collectively, these observations indicate that psychosine plays pathological roles in the nervous tissues as well as in the periphery. The receptor for psychosine has been shown to be the same as TDAG8, a heptahelical receptor that binds heterotrimeric G proteins [106 ]. TDAG8 is up-regulated during apoptosis of immature thymocytes as a result of activation with anti-CD3 plus anti-CD28 or with glucocorticoids [107 ] and is mainly expressed in lymphoid tissues [106 107 108 ].


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EXPRESSION OF RECEPTORS FOR LYSOLIPIDS IN NK CELLS
 
We have recently reported that resting as well as IL-2-activated NK cells express S1P1, S1P4, and S1P5 but not S1P2 or S1P3, the receptors for S1P [109 ]. These cells also express LPA1, LPA2, and LPA3, the receptors for LPA (manuscript submitted). The function of these receptors is manifested by the ability of S1P or LPA to induce the chemotaxis of migrating NK cells (ref. [109 ], and manuscript submitted). This function is inhibited by pretreatment of NK cells with PTX, indicating that members of Gi/o are involved in the chemoattraction induced by these phospholipids, although PTX-insensitive G proteins are also involved in mediating S1P-induced NK cell chemotaxis [109 ]. Surprisingly, we observed that S1P or LPA inhibits activated NK cell lysis of tumor target cells in a 4-h 51Cr relesae assay (submitted). In contrast, chemokines such as RANTES and TARC enhance NK cell-mediated killing, supporting earlier findings [34 , 110 ]. These results indicate that phospholipids perform at least dual functions in NK cells. These are recruitment of the cytolytic NK cells and inhibition of their cytolytic activity against tumor cells. Receptors for lysophospholipids S1P and LPA may not be the only ones expressed in NK cells. In addition to S1P1,4,5 and LPA1,2,3, we recently observed that resting as well as activated NK cells express TDAG8 and determined that NK cells respond chemotactically to psychosine and to the related lipids such as glucosylated and lactosylated sphingosine (unpublished observations). Whether NK cells express OGR1 and G2A, the receptors for SPC and LPC, and whether SPC and LPC perform similar function to S1P and LPA in NK cells are interesting issues that need to be investigated. This is important in lieu of the fact that LPC induces the recruitment of T cells into the arterial walls, resulting in the secretion of IFN-{gamma}, which is responsible for the inflammation associated with atherosclerosis [98 ]. As NK cells are the major cells secreting IFN-{gamma}, it remains to be seen whether NK cells may participate in the process of atherosclerosis.

To reiterate, it appears that lysolipids, whether phosphorylated or glycosylated, perform similar functions to chemokines in NK cells, which are the induction of their recruitment and chemotaxis, corroborated with the mobilization of intracellular calcium. Similar to chemokines, these lipids use heterotrimeric G proteins to perform these functions. However, a major difference became apparent in other cellular responses. In contrast to chemokines that activate NK cells to kill tumor target cells after a short-term [34 , 110 ] or after a prolonged period [111 ], lysolipids inhibit NK cell-mediated cytotoxicity in short-term cultures. Therefore, tumor cells that highly secrete lysolipids may have developed a strategy to control the cytolytic activity of the anti-tumor effector cells. It is not clear why molecules secreted by tumor cells would attract the anti-tumor effector cells toward the sites of tumor growth. As indicated in the chemokine section, NK cells may provide a suitable environment for the survival of tumor cells, which may include the secretion of cytokines such as IFN-{gamma} or IL-2, which could promote the growth of tumors. In this regard, although S1P inhibits the proliferation of polyclonal T cells, it enhances the secretion of IFN-{gamma} and IL-2 by these cells [112 ].


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CONCLUDING REMARKS
 
NK cells express at least two types of GPCR: receptors for chemokines and receptors for lysolipids. For chemokine receptors, resting NK cells mainly express constitutive chemokine receptors that allow them to reside in various tissues such as the spleen. However, only a subset of these cells that expresses CD56dim and ß2integrinbright is capable of in vivo binding to vascular endothelium. Under pathological conditions where inflammatory cytokines are present, these cells are induced to express inflammatory chemokine receptors. Subsequently, they start their sojourn into inflammatory, tumor, or virally infected sites where inflammatory chemokines are secreted in large quantities. The function of these cells is to eradicate the host from infections or tumor metastases. Chemokines that are secreted by infected or tumor cells enhance the cytolytic activity of these cells. In addition, resting and activated (including AD-) NK cells express receptors for phosphorylated lysolipids (S1P and LPA) and galactosylated sphingosine (psychosine). These lipids, which are secreted by tumor cells and are up-regulated during pathological conditions, recruit NK cells. In contrast to chemokines, lysolipids inhibit the cytolytic function of NK cells and hence, provide a favorable environment for the growth of tumor cells, where NK cells secrete cytokines that may promote the growth of tumors. It is not yet clear whether NK cells present at the sites of tumors may down-regulate the expression of lysolipid receptors as a result of the high secretion of lysolipids at these sites. This and other issues may form highly interesting and important areas for future investigations to advance our understanding of NK cell (host)/tumor cell interactions. Consequently, we should be able to learn how carcinogenesis and angiogenesis proceed in the presence of the anti-tumor effector cells. This understanding may lead to novel modalities for the prevention and treatment of various immunological diseases.


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ACKNOWLEDGEMENTS
 
The European Community (Grant QLRT-2000-02103) and the Norwegian Cancer Society (Grant 97025/002) supported the work in the author’s laboratory. My sincere thanks go to Dr. Bent Rolstad and to the members of my laboratory for critically reading this article and for correcting my mistakes.

Received January 15, 2003; revised February 28, 2003; accepted March 1, 2003.


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