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(Journal of Leukocyte Biology. 2002;71:173-183.)
© 2002 by Society for Leukocyte Biology

Role of chemokines in the biology of natural killer cells

Michael J. Robertson

Bone Marrow and Stem Cell Transplantation Program and Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis

Correspondence: Michael J. Robertson, M.D., Bone Marrow and Stem Cell Transplantation Program, 1044 W. Walnut Street, Room R4-202, Indianapolis, IN 46202. E-mail: mjrobert{at}iupui.edu


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ABSTRACT
 
Natural killer (NK) cells participate in innate and adaptive immune responses to obligate intracellular pathogens and malignant tumors. Two major NK cell subsets have been identified in humans: CD56dim CD16+ and CD56bright CD16-. Resting CD56dim CD16+ NK cells express CXCR1, CXCR2, CXCR3, CXCR4, and CX3CR1 but no detectable levels of CC chemokine receptors on the cell surface. They migrate vigorously in response to CXCL12 and CXC3L1. In contrast, resting CD56bright CD16- NK cells express little CXCR1, CXCR2, and CXC3R1 but high levels of CCR5 and CCR7. Chemotaxis of CD56bright CD16- NK cells is stimulated most potently by CCL19, CCL21, CXCL10, CXCL11, and CXCL12. Following activation, NK cells can migrate in response to additional CC and CXC chemokines. Cytolytic activity of NK cells is augmented by CCL2, CCL3, CCL4, CCL5, CCL10, and CXC3L1. Moreover, proliferation of CD56dim CD16+ NK cells is costimulated by CCL19 and CCL21. Activated NK cells produce XCL1, CCL1, CCL3, CCL4, CCL5, CCL22, and CXCL8. Chemokines secreted by NK cells may recruit other effector cells during immune responses. Furthermore, CCL3, CCL4, and CCL5 produced by NK cells can inhibit in vitro replication of HIV. CCL3 and CXL10 expression appear to be required for protective NK cell responses in vivo to murine cytomegalovirus or Leishmania major, respectively. Moreover, NK cells participate in the in vivo rejection of transduced tumor cells that produce CCL19 or CCL21. Thus, chemokines appear to play an important role in afferent and efferent NK cell responses to infected and neoplastic cells.

Key Words: chemotaxis • cytotoxicity • proliferation


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INTRODUCTION
 
Natural killer (NK) cells, such as T and B cells, are one of the major lymphocyte subsets that have been identified in all vertebrate species examined [1 2 3 ]. Unlike T and B lymphocytes, however, NK cells do not productively rearrange T-cell receptor or immunoglobulin genes and do not appear to express highly variable, antigen-specific receptors. Nevertheless, NK cells can discriminate between normal cells and neoplastic or virus-infected cells [1 2 3 ]. NK cells participate in innate immune responses that can inhibit intracellular pathogens while antigen-specific T- and B-cell responses are generated [4 5 6 ]. Moreover, NK cells secrete cytokines, such as interferon-{gamma} (IFN-{gamma}), which promote the differentiation of activated CD4 T cells into Th1 helper effector cells [4 , 5 , 7 ]. NK cells can also contribute to the elimination of infected cells during the effector phase of adaptive immune responses [1 2 3 ]. NK cells can recognize and destroy cancer cells that have evaded cytotoxic T lymphocytes (CTL) [8 ]. Thus, NK cells participate in innate and adaptive immune responses to intracellular pathogens and malignant tumors.

The cytolytic activity of NK cells is clearly distinguishable from that mediated by typical CTL: It occurs spontaneously (i.e., in the absence of deliberate, prior immunization) and does not require expression of syngeneic major histocompatibility complex (MHC) antigens by target cells. Recently, the molecular basis for target-cell recognition by human and murine NK cells has been elucidated [2 , 8 9 10 ]. Unlike CTL, NK cells do not appear to express one dominant receptor that dictates the specificity of cytolysis. Rather, triggering of NK cell cytotoxicity reflects a balance between activating and inhibitory signals mediated by cell-surface receptors that belong to several different gene families. Inhibitory MHC class I receptors have a central role in current paradigms of target-cell recognition by NK cells [2 , 8 9 10 ]. Ligation of these inhibitory receptors by specific MHC class I allotypes delivers a dominant-negative signal to NK cells that prevents natural killing. Down-regulation of MHC class I molecules on the target-cell surface, which commonly occurs during viral infection or neoplastic transformation, releases the NK cell from inhibitory signals and allows lysis of the aberrant target cell. Positive signals for cytolysis are provided by ligation of several activating receptors (e.g., CD2, CD16, NKR-P1, 2B4, NKp30, NKp44, and NKp46) expressed by NK cells [2 , 9 , 10 ]. However, the contribution of these putative activating receptors to triggering NK cytolysis in vivo has not been well-defined.

Like T cells, NK cells are heterogeneous with respect to functional activity and cell-surface antigen expression [11 12 13 14 ]. Two major NK cell subsets have been identified in humans. CD56dim NK cells, comprising about 90% of peripheral blood NK cells, express the CD16 antigen at high density but relatively low levels of CD56. Freshly isolated, unstimulated CD56dim NK cells mediate natural killing and antibody-dependent cellular cytotoxicity (ADCC). CD56dim NK cells express ß {gamma} common chains of the interleukin (IL)-2 and IL-15 receptors and demonstrate augmented cytotoxicity, proliferation, and cytokine secretion after stimulation with IL-2 or IL-15 [11 12 13 , 15 ]. However, CD56dim NK cells produce relatively little IFN-{gamma} after stimulation with IL-2 or IL-15 in combination with IL-12. CD56bright NK cells express high-affinity IL-2 receptor {alpha} ß {gamma} heterotrimers but little or no CD16. CD56bright NK cells proliferate vigorously in response to IL-2 alone [11 12 13 ] and produce abundant amounts of IFN-{gamma} after stimulation with IL-2 or IL-15, together with IL-12. In contrast, CD56bright NK cells exhibit weak cytolytic activity when freshly isolated. These observations support the hypothesis that CD56bright NK cells, like CD4 T cells, predominantly regulate other cells through cytokine production [14 , 16 ]. In contrast, CD56dim NK cells, like CD8+ CTL, are terminally differentiated cytotoxic-effector cells.

The CD56bright and CD56dim NK cell subsets can be reliably distinguished only for resting human NK cells. The CD56 antigen is up-regulated on CD56dim NK cells following activation in vitro or in vivo [17 18 19 20 21 ]. Thus, the density of CD56 on the cell surface cannot be used to discriminate unstimulated CD56bright NK cells from activated CD56dim NK cells. Moreover, subsets analogous to CD56bright and CD56dim NK cells in humans have not been identified in mice or other species. It should be noted that murine NK cells do not express CD56, so this molecule cannot be required for NK cell function in vivo.

To mediate their cytolytic function effectively, NK cells must be recruited to the site of infected or neoplastic cells. Moreover, to regulate the adaptive immune response, cytokine-secreting NK cells must be in intimate proximity to antigen-stimulated T and/or B cells. Nevertheless, until recently, very little was known about the regulation of NK cell migration and trafficking. Work done in several laboratories over the past few years has implicated chemokines as key regulators of NK cell migration and function.


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CHEMOKINES AND THEIR RECEPTORS
 
Chemokines are a group of at least 47 related proteins, making them the largest family of cytokines known [22 23 24 25 26 27 ]. Depending on the number and spacing of conserved cysteine residues in their amino acid sequence, chemokines have been classified into four major groups: the CXC (or {alpha}), CC (or ß), CX3C, and C subfamilies. The CXC and CC subfamilies have been subdivided further according to structural homologies and biological activities. Chemokines exert their biologic effects by binding to specific cell-surface receptors. The chemokine receptors, which have also been classified into four subfamilies, are G-protein-coupled seven-transmembrane-spanning molecules. A single chemokine can bind to more than one receptor, and a given receptor can interact with multiple chemokines. Together with the large number of chemokines and receptors, this poses a formidable challenge for investigators seeking to elucidate the physiologic role of chemokines in vivo.

Chemokines play a crucial role in coordinating adaptive immune responses. Chemokines regulate the migration of immature lymphoid progenitor cells, the recirculation of mature naive T and B lymphocytes, and the homing of antigen-specific effector T cells. Chemokines also control the migration of antigen-presenting cells, including dendritic cells and cells of monocyte/macrophage lineage [22 23 24 25 26 27 ]. Other important physiologic and pathophysiologic activities of chemokines include inhibition or promotion of angiogenesis, regulation of tumor metastasis, inhibition of hematopoietic progenitor cell proliferation, and modulation of HIV infection. A detailed discussion of chemokine biology is beyond the scope of this review. Interested readers are referred to recent review articles devoted to chemokines and their receptors [22 23 24 25 26 27 28 ].

Inconsistency and bewildering complexity have characterized the nomenclature of chemokines and their receptors in the past. It is not uncommon to encounter from three to more than five different synonyms being used in the literature to refer to the same chemokine. Recently, a uniform and widely accepted nomenclature has been adapted [23 , 27 , 29 ]. Common synonyms for some chemokines that have been shown to affect NK cell function are summarized in Table 1 .


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  		Table 1. Synonyms for Selected Chemokines with NK Cell Activity


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CHEMOKINE RECEPTORS EXPRESSED BY NK CELLS
 
The expression of chemokine receptors by human NK cells is a subject of controversy. The two most comprehensive studies that have been published to date provide contradictory results, particularly with respect to the CXC chemokine receptors. Campbell et al. [30 ] found that most human NK cells express high levels of CXCR1, CXCR4, and CX3CR1; CXCR2 and CXCR3 were expressed at lower levels. Several other groups have also described expression of CXCR1 and CXCR2 [31 , 32 ] or CX3CR1 [33 , 34 ] by resting human NK cells. In contrast, Inngjerdingen et al. [35 ] found that purified, resting human NK cells expressed CXCR4 but not CXCR1, CXCR2, CXCR3, or CX3CR1. It is not clear why Inngjerdingen et al. [35 ] failed to detect CXCR1, CXCR2, and CX3CR1 on resting human NK cells. It is possible that levels of these chemokine receptors were down-regulated during the isolation of purified NK cells by their methods; this phenomenon has been noted by another group [36 ].

The published data are more consistent with respect to NK cell expression of the CC chemokine receptors. As assessed by flow cytometry using specific antibodies, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, and CCR9 are not expressed at significant levels on the surface of most resting human NK cells [30 , 35 , 37 ]. CCR2, CCR4, CCR5, and CCR8 are expressed by human NK cells after in vitro activation with IL-2 or IL-15 [35 , 37 , 38 ].

Recent studies have clarified the expression of CCR7 and response to the CCR7 ligands, CCL19 and CCL21, by human NK cells. Several groups have demonstrated that CCL19 and CCL21 do not stimulate significant chemotaxis of resting peripheral blood NK cells [39 40 41 ]. Moreover, message for CCR7, as assessed by Northern blot or reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, was not detected in resting NK cells [40 , 41 ]. In contrast, Kim et al. [42 ] found that CCL19 and CCL21 stimulated the migration of the CD16- subset of cord blood and adult peripheral blood NK cells. CD56bright CD16- NK cells normally comprise only ~10% of the total peripheral blood NK cell population, and selective chemotaxis of this subset is obscured readily by the relatively high, spontaneous migration of the much more numerous CD56dim CD16+ NK cells [39 ]. However, Kim et al. [42 ] isolated adult and cord blood NK cells by positive selection using CD56 beads, which greatly enriches the proportion of CD56bright CD16- NK cells among the total NK cell population [43 ]. Subsequent work has confirmed that CD16- but not CD16+ resting human NK cells express CCR7 on the cell surface and migrate vigorously in response to CCL19 and CCL21 [30 ]. Results from the author’s laboratory (unpublished results) are concordant with those of Campbell et al. [30 ] with respect to expression of CCR6 and CCR7 by resting CD56bright and CD56dim NK cells.

In contrast to results of others [30 , 41 ] and our unpublished data, Inngjerdingen et al. [35 ] have demonstrated that the majority of resting human NK cells expresses CCR7. However, Inngjerdingen et al. [35 ] used a polyclonal antibody recognizing the carboxy terminus of CCR7 to stain permeabilized NK cells. Thus, the CCR7 molecules detected by this method may be located intracellularly rather than on the cell surface.

In addition to CCR7, other chemokine receptors are expressed differentially by the CD56bright CD16- and CD56dim CD16+ subsets of human NK cells (Table 2 ). Unlike the great majority of resting NK cells, the rare CD56bright CD16- subset does not express CXCR1, CXCR2, or CX3CR1 but does express CCR5 [30 ]. As expected, based on the known biology of chemokine receptors, chemotaxis of NK cells stimulated by chemokines is inhibitable by Bordetella pertussis toxin [42 , 44 , 45 ]. Chemokine signaling in NK cells involves several guanine nucleotide-binding proteins and leads to intracellular calcium ion mobilization [45 46 47 48 ].


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  		Table 2. Expression of Chemokine Receptors by Resting Human NK Cells


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REGULATION OF NK CELL MIGRATION BY CHEMOKINES
 
Numerous chemokines have been shown to stimulate the migration of NK cells as determined by in vitro chemotaxis assays (Tables 3 and 4 ). Results with the CXC chemokines agree well with the data on CXC chemokine receptor expression by NK cells. Thus, resting human NK cells have been found to migrate in response to known ligands for CXCR3 (CXCL9, CXCL10, and CXCL11) and CXCR4 (CXCL12) [30 , 35 , 36 , 39 , 42 , 49 ]. Furthermore, chemotaxis of resting NK cells is stimulated by XCL1 and CX3CL1 [30 , 35 , 50 ]. Although CXCR1 and CXCR2 appear to be expressed by most resting human NK cells [30 31 32 ], the responsiveness of the latter to CXCL1 or CXCL8 is a subject of controversy. Some investigators have shown that resting NK cells can migrate in response to CXCL1 [35 ] or CXCL8 [30 ]; other investigators have found these chemokines to have inconsistent, donor-dependent effects on resting NK cells [36 ]. Furthermore, CXCL8 may not stimulate the chemotaxis of human NK cells that have been activated in vitro [35 , 47 ].


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  		Table 3. Migration of Resting NK Cells in Response to Chemokines


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  		Table 4. Chemokines Reported to Stimulate Migration of Activated NK Cells

Resting human NK cells also migrate in response to several CC chemokines, including CCL2, CCL3, CCL4, CCL5, CCL7, and CCL8 [35 , 36 , 44 , 51 ], although known receptors for the latter are generally undetectable on most resting NK cells [30 , 35 , 37 ]. However, results with the CC chemokines are not consistent in the published literature: Some investigators have demonstrated positive findings using activated but not resting NK cells [44 , 47 ]. It is possible that some of the known CC chemokine receptors are actually expressed on the surface of resting NK cells but at levels below the limits of detection by routine flow cytometry. Alternatively, resting NK cells may express as-yet uncharacterized novel receptors for some of the CC chemokines. After in vitro activation, human NK cells up-regulate CCR2, CCR4, CCR7, and CCR8 [35 , 37 , 38 , 40 , 52 ] and demonstrate increased chemotactic responses to known ligands of these receptors, including CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL19, CCL21, and CCL22 [35 , 40 , 44 , 47 , 53 ].

Differences in the chemotactic responses of resting CD56bright and CD56dim NK cells correlate well with known differences in their expression of chemokine receptors [30 ]. Compared with CD56dim NK cells, CD56bright NK cells express higher levels of CXCR3 and respond more vigorously to CXCL10 and CXCL11. Conversely, CD56bright NK cells express little or no CXCR1, CXCR2, and CX3CR1 and do not migrate in response to CXCL8 or CX3CL1. As discussed above, CD56bright NK cells but not CD56dim NK cells express CCR7 and respond to CCL19 and CCL21 [30 , 42 ].

In contrast to the abundant in vitro studies, published data on in vivo migration of NK cells in response to chemokines are sparse. Intraperitoneal (i.p.) injection of murine XCL1 induces transient influx of lymphocytes into the peritoneal cavity [54 ]. The majority of these lymphocytes are mature NK cells. However, freshly isolated murine NK cells did not migrate in vitro in response to XCL1 [54 ]. Therefore, additional factors, perhaps induced by the local trauma of i.p. injection, may act in concert with XCL1 to stimulate chemotaxis of murine NK cells in vivo. As discussed in detail below, CCL3 promotes in vivo migration of activated NK cells into the livers of mice infected with murine cytomegalovirus (MCMV) [6 , 55 ].


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REGULATION OF NK CELL CYTOTOXICITY BY CHEMOKINES
 
NK cells mediate antibody-dependent and -independent lysis of target cells [1 , 2 , 9 , 10 ]. Resting NK cells can lyse antibody-coated target cells by ADCC. The receptor on NK cells that triggers ADCC is a multimolecular complex composed of CD16, a low-affinity receptor for the Fc portion of immunoglobulin, in noncovalent association with homodimers or heterodimers of the {zeta} family of signaling molecules. Resting NK cells can also spontaneously lyse NK-sensitive target cells by an antibody-independent process known as natural killing or NK activity [1 , 2 , 9 , 10 ]. Sensitivity to natural killing is the property of certain virus-infected and neoplastic-hematopoietic cells; most normal cells and malignant epithelial cells are NK-resistant. Nevertheless, after exposure to exogenous cytokines (such as IL-2, IL-12, or IL-15), NK cells can lyse solid tumor cells that are resistant to lysis by unstimulated NK cells [15 , 18 , 56 ]. This cytolytic activity has been called lymphokine-activated killer (LAK) activity.

Relatively few chemokines have been shown to enhance the cytolytic activity of NK cells (Table 5 ). Taub et al. [36 , 57 ] found that CCL3 and CXCL10 consistently augmented the lysis of NK-sensitive K562 cells by purified, human NK cells. Enhancement of natural killing by these cytokines was inferior to that produced by optimal concentrations of IL-2. CCL2, CCL4, and CCL5 were also found to stimulate greater levels of natural killing, albeit less consistently and in a donor-dependent fashion. Unlike IL-2, none of these chemokines were found to augment ADCC or induced the lysis of NK-resistant targets by human NK cells. CX3CL1 has also been shown to modestly increase NK cell cytotoxicity toward NK-sensitive target cells [33 ].


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  		Table 5. Effect of Chemokines on NK Cell Cytotoxicity

Maghazachi et al. [58 ] have shown that CCL2, CCL3, CCL4, and CCL5 can augment cytotoxicity of enriched CD56+ human NK cells. In contrast to the results of Taub et al. [36 ], these investigators found that the effects of CCL2, CCL3, and CCL5 were comparable with those of optimal concentrations of IL-2 and that chemokines could stimulate lysis of NK-sensitive and NK-resistant target cells.

The mechanisms by which chemokines augment NK cell cytolytic activity have not been fully elucidated. Lysis of target cells by NK cells occurs in three phases [1 , 2 , 9 , 10 ]. First, NK cells must bind to potential target cells via interactions between NK cell-surface adhesion molecules [e.g., lymphocyte function-associated antigen-1 (LFA-1) and CD2] and their cognate target-cell ligands [e.g., intercellular adhesion molecules (ICAM)-1, -2, and -3 and CD58]. Next, positive signals from ligation of activating receptors (e.g., CD16) must outweigh negative signals from ligation of inhibitory receptors. Finally, NK cells must express apoptosis-inducing ligands (e.g., CD95 ligand) and/or must discharge their cytotoxic granules against the target-cell membrane [59 ]. NK cell cytotoxic granules contain perforin and granzymes, which can induce apoptosis and necrosis of target cells.

CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CXCL10, and CX3CL1 have been shown to promote cytotoxic granule release by resting polyclonal human NK cells or NK cell clones [33 , 36 , 47 ]. Concentrations of chemokines that stimulate granule exocytosis were similar to those that enhance NK cell cytolytic activity. Thus, chemokines may augment NK cell lysis of target cells, in part, by facilitating the discharge of NK cell cytotoxic granules. Augmentation of NK cell cytotoxicity by CX3CL1 was not associated with up-regulation of LFA-1, CD2, or other adhesion molecules on NK cells [33 ]. However, several CC chemokines known to augment NK cell cytotoxicity have been found to induce redistribution of adhesion molecules on the NK cell surface [37 ]. Nevertheless, the effects of chemokines on NK cell adhesion-molecule expression and their conjugate formation with target cells have not been described in detail and merit further investigation. Moreover, it is currently not known whether chemokines affect signals that are transduced after ligation of activating or inhibitory NK cell receptors.


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REGULATION OF NK CELL PROLIFERATION BY CHEMOKINES
 
Human NK cells can be induced to proliferate in response to IL-2, IL-4, IL-7, IL-12, and IL-15 [15 , 18 , 60 , 61 ]. However, NK cell proliferation to IL-2 and IL-15 is about tenfold greater than proliferation to other mitogenic cytokines. Thus, signals mediated through the common IL-2/IL-15 ß {gamma} receptor appear to provide the strongest proliferative stimulus for human NK cells. Like proliferation of T and B lymphocytes, the proliferation of NK cells appears to require costimulatory signals as well as primary mitogenic signals. Costimulation of NK cell proliferation can be provided by soluble cytokines, ligation of defined cell-surface receptors, or contact with certain stimulator cells [60 61 62 63 64 ].

None of the chemokines that have been tested so far, including CCL2, CCL3, CCL4, CCL5, CCL19, CCL20, CCL21, and CXCL8, have been found to stimulate the proliferation of purified, resting NK cells [40 , 58 ]. CCL2, CCL3, CCL4, and CCL5 can induce the proliferation of nylon-wool column-nonadherent peripheral blood lymphocytes (PBL), which contain mostly T and NK cells [58 ]. Purified CD4 and CD8 T cells did not proliferate in response to CC chemokines. Furthermore, CCL3- and CCL5-induced proliferation of PBL was abrogated by the presence of neutralizing anti-IL-2 antibody. Thus, it has been speculated that CC chemokines can stimulate T-cell secretion of IL-2, which then indirectly stimulates the proliferation of NK cells [58 ].

Little has been published regarding the ability of chemokines to costimulate NK cell proliferation in response to primary mitogens. The two known CCR7 ligands, CCL19 and CCL21, can costimulate IL-2-induced proliferation of CD56dim NK cells [40 ]. Such costimulation was dose-dependent and was of moderate magnitude. No effect of CCL19 or CCL21 on the more robust proliferation of CD56bright NK cells in response to IL-2 was detected [40 ]. Moreover, CCL20 in doses as high as 1000 ng/ml did not affect IL-2-induced proliferation of CD56dim or CD56bright NK cells.


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CHEMOKINES PRODUCED BY NK CELLS
 
In addition to responding to numerous chemokines, NK cells have been found to produce several chemokines (Table 6 ). Human peripheral blood NK cells cultured in the absence of deliberate stimuli can spontaneously produce CCL4, CCL5, and CCL22 in vitro [37 , 65 66 67 68 ]. Unstimulated normal human NK cells express mRNA for CCL3 [66 ], but appear to produce little if any CCL3 protein [65 , 69 ]. Resting human NK cells also express mRNA for XCL1 [35 , 70 ], but XCL1 protein was not detected in the cytoplasm of unstimulated murine NK cells [54 ]. CD56bright CD16- NK cells isolated from human uterine decidua spontaneously express CXCL8 mRNA and secrete CXCL8 protein [71 ]. It is currently not known whether peripheral blood CD56bright CD16- or CD56dim CD16+ NK cells spontaneously produce CXCL8.


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  		Table 6. Production of Chemokines by NK Cellsa

After in vitro activation, NK cells produce greater amounts of CCL4, CCL5, CCL22, and CXCL8 and also produce XCL1, CCL1, and CCL3 [37 , 54 , 65 66 67 68 69 , 72 73 74 75 76 ]. Based on these results, it is expected that T cells, B cells, NK cells, neutrophils, and several other cell types could be attracted to the vicinity of activated NK cells. In fact, little has been published about the ability of activated NK cells to attract other cells in vitro or in vivo. Supernatants from activated human NK cells stimulate the in vitro migration of CD4 T cells, CD8 T cells, and neutrophils [76 ]. CXCL8 produced by activated NK cells was found to be partially but not completely responsible for the observed T-cell chemotaxis. Nieto et al. [37 ] have shown that IL-2-activated human NK cells can induce the chemotaxis of other NK cells. Moreover, interaction between NK cells and NK-sensitive K562 target cells stimulated greater production of CCL3, CCL4, and CCL5 [37 , 66 ] and a concomitant increase in the migration of bystander NK cells [37 ]. These data suggest that NK cell interaction with target cells can stimulate secretion of chemokines that promote the recruitment of additional NK cells to sites of infected or transformed cells.

CCR5 is a coreceptor for macrophage-tropic (M-tropic) strains of HIV-1 [25 ]. Ligands for CCR5, including CCL3, CCL4, and CCL5, have been shown to inhibit the infection of human cells by M-tropic HIV-1 strains. Because activated human NK cells can produce CCL3, CCL4, and CCL5, it is possible that NK cells could be manipulated with therapeutic intent in the treatment of HIV-1 infection. Indeed, activated NK cells from HIV-infected persons have been shown to suppress HIV replication in autologous lymphocytes in vitro [66 ]. Furthermore, HIV-1 replication in normal PBL is inhibited potently in vitro by supernatants of activated NK cells from HIV-infected or normal control donors [65 ]. The effects of activated NK cells or their supernatants on HIV replication are partially but not completely reversed by the presence of neutralizing antibodies to CCL3, CCL4, and CCL5 [65 , 66 ]. Thus, NK cells may inhibit HIV replication by secreting CCL3, CCL4, and CCL5 as well as other chemokines or soluble-effector molecules.


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PARTICIPATION OF CHEMOKINES IN NK CELL RESPONSES TO INFECTION AND CANCER
 
Elegant work has demonstrated the crucial role of chemokines in the adaptive immune response and the biology of T and B lymphocytes [22 23 24 25 26 ]. For example, antigen-specific T- and B-cell responses are impaired severely in CCR7-deficient mice [77 ]. This impairment does not appear to be caused by intrinsic defects in mature T or B lymphocytes, but rather the failure of T cells, B cells, and dendritic cells to migrate appropriately to secondary lymphoid tissues [77 ]. In contrast, the effects of deficiencies of specific chemokines or chemokine receptors on NK cell development and function have not been described in detail. Therefore, the role of chemokines in NK cell biology in vivo must be inferred from indirect evidence.

An exception to this limitation is the clearly defined role of CCL3 in NK cell-mediated protection from MCMV. NK cells become activated in vivo early in the course of MCMV infection, and protective antiviral immune responses require IFN-{gamma} produced by NK cells [5 ]. Migration of NK cells into the liver is necessary for successful clearance of MCMV infection [6 , 55 ]. Expression of CCL3 mRNA and protein is induced in the murine liver following MCMV infection, and migration of adoptively transferred NK cells to the liver of MCMV-infected mice is abrogated by administration of neutralizing anti-CCL3 antibody [55 ]. Moreover, migration of NK cells to the liver, local IFN-{gamma} production, and NK cell-dependent antiviral protection are markedly diminished in CCL3-deficient mice infected with MCMV [6 , 55 ]. CCL3-deficient mice uniformly succumb to MCMV infection, whereas wild-type mice control the infection and survive. Serum IFN-{gamma} levels are the same in CCL3-deficient and wild-type mice, indicating that local IFN-{gamma} production in the liver is critical for control of MCMV infection.

Abundant production of CXCL9 occurred in the livers of wild-type but not CCL3-deficient mice after MCMV infection [6 ]. Depletion of NK cells strongly inhibited this CXCL9 production. Furthermore, CXCL9 production was not detected in the livers of IFN-{gamma}-deficient mice infected with MCMV. Therefore, it is likely that local secretion of IFN-{gamma} in the liver by activated NK cells is responsible for CXCL9 production during MCMV infection. Furthermore, neutralization of CXCL9 in vivo was associated with a marked increase in MCMV titers in the liver and a fatal outcome [6 ]. Thus, protective immune responses to MCMV require expression of CCL3 in the liver to attract activated NK cells, local IFN-{gamma} secretion by activated NK cells, and subsequent production of CXCL9 in the liver. Local production of CXCL9 and CXCL10 can also stimulate NK cell-dependent protective responses to recombinant vaccinia viruses in vivo [78 ].

The cell types in the liver that produce CXCL9 during MCMV infection have not been identified clearly, but hepatocytes can produce this chemokine [79 ]. Moreover, a fourfold increase in liver NK cell numbers was observed in MCMV-infected as compared with uninfected CCL3-deficient mice [6 ]. Although this degree of NK cell infiltration is apparently not sufficient for ultimate control of MCMV, it suggests that factors other than CCL3 can stimulate NK cell migration into the liver in vivo.

Leishmania major is an obligate intracellular pathogen that can cause cutaneous or disseminated disease. Resistant strains of mice, such as C57BL/6, develop a Th1-dominated immune response to this pathogen and recover from infection [4 , 80 , 81 ]. Conversely, susceptible strains, such as Balb/c, develop Th2 responses and succumb to disseminated disease. It has been shown that IFN-{gamma} produced by activated NK cells in reactive lymph nodes promotes protective Th1 immune responses to L. major [4 ]. Moreover, parasite burden is correlated inversely with the level of NK cell cytotoxicity present in regional lymph nodes. Susceptibility of Balb/c mice appears to be a result of, at least in part, defective NK cell activation at the site of infection as a consequence of inadequate, local IL-12 production by macrophages [80 ]. However, failure to activate NK cells properly in draining lymph nodes could also contribute to fatal leishmaniasis. Following infection with Leishmania, lower NK cell cytotoxicity is observed in the draining lymph nodes of susceptible Balb/c mice as compared with resistant C57BL/6 mice [4 , 82 ], although the number of NK cells present does not differ between the two strains [82 ]. Message for XCL1, CCL2, and CXCL10 is expressed in draining lymph nodes from resistant but not susceptible mice during the early phases of Leishmania infection [82 ]. Furthermore, local injection of CXCL10 in vivo augmented NK cytotoxicity in the draining lymph nodes of Balb/c mice infected with Leishmania [82 ]. Thus, defective production CXCL10 and other chemokines in regional lymph nodes, with subsequent, inadequate stimulation of NK cell cytotoxicity and/or cytokine production, may contribute to the susceptibility of Balb/c mice to Leishmania infection.

In addition to their crucial role in the response to some obligate intracellular pathogens, NK cells can contribute to the rejection of malignant tumors. Preclinical animal models indicate that chemokines participate in the NK cell response to cancer. Systemic administration of IL-12 can induce the complete regression of established tumors, inhibit the formation of distant metastases, and prolong the survival of tumor-bearing mice [83 ]. Depending on the experimental system used, CD4 T cells, CD8 T cells, and NK cells have been found to contribute to the antitumor activity of IL-12. Furthermore, production of IFN-{gamma} in vivo is necessary but not sufficient for the antitumor effects of IL-12 [84 , 85 ]. IFN-{gamma} secreted by IL-12-activated T and NK cells can in turn stimulate the production of several cytokines including CXCL9 and CXCL10. The latter are required for tumor regression during IL-12 therapy [86 ]. The antitumor effects of CXCL9 and CXCL10 are due to recruitment of CXCR3-bearing antitumor-effector cells as well as the inhibition of tumor angiogenesis [86 87 88 89 ]. Thus, CXCL9, CXCL10, and possibly other chemokines can participate in NK cell-mediated antitumor effects during cytokine-based immunotherapy for cancer.

Systemic administration of immunostimulatory cytokines can be associated with substantial toxicity [90 ]. An alternative approach for cancer immunotherapy is vaccination with cytokine gene-transduced tumor cells. Injection of tumor cells transduced with genes encoding one or more of several immunostimulatory cytokines can stimulate the rejection of established, nontransduced tumors and promote durable, specific antitumor immunity [91 , 92 ]. Antitumor effects have also been observed after vaccination with chemokine gene-transduced tumor cells. Transduction of the C26 murine-colon adenocarcinoma cell line with a cDNA encoding CCL21 does not affect the in vitro growth of the malignant cells but does reduce their tumorigenicity in vivo [93 ]. Depletion of CD8 T cells or NK cells in vivo led to more rapid growth of tumors, indicating that both lymphocyte subsets participate in the response to CCL21-transduced C26 cells. CCR7 and CXCR3 are receptors for CCL21 in the mouse [39 , 94 ]. Expression of CCR7 mRNA but not CXCR3 mRNA was increased dramatically in tumors formed by CCL21-transduced C26 cells as compared with nontransduced cells [93 ]. These results suggest that paracrine secretion of CCL21 by transduced C26 cells recruits CCR7-expressing effector cells, which then inhibit tumor cell growth.

CCR7 is a receptor for CCL19 as well as CCL21. Transduction of the C3L5 murine-breast adenocarcinoma cell line with a cDNA encoding CCL19 substantially reduces its tumorigenicity in vivo without affecting its in vitro growth [95 ]. NK cells and to a lesser degree CD4 T cells contribute to the rejection of CCL19-transduced C3L5 cells; CD8 T cells do not appear to be involved. Vaccination with CCL19-transduced tumor cells does not confer protection from subsequent rechallenge with nontransduced C3L5 cells, although the latter grow more slowly in vaccinated compared with nonvaccinated animals [95 ]. In contrast to the initial rejection of CCL19-transduced cells, partial immunity to rechallenge with nontransduced C3L5 appears to be mediated entirely by CD4 T cells, without participation of NK cells or CD8 T cells.

In preclinical models using the Meth A fibrosarcoma or HM-1 ovarian carcinoma cell lines, injection with tumor cells transduced with cDNA encoding CCL19, CCL21, or CXCL12 appeared to augment antitumor immune responses evoked by vaccination with tumor cells expressing IL-2 or granulocyte-macrophage colony-stimulating factor (GM-CSF) [96 ]. In agreement with the C26 and C3L5 models [93 , 95 ], vaccination with chemokine-expressing tumor cells alone did not stimulate durable, protective antitumor immunity [96 ].

Transduction of the CCL2 gene has also been demonstrated to alter the tumorigenicity or immunogenicity of malignant cells in several models [97 98 99 ]. Suppression of tumor formation [98 ] and metastasis [99 ] by CCL2-transduced cells in T-cell-deficient nu/nu or SCID mice suggests a response by innate immune effectors such as NK cells and monocytes. Indeed, NK cells have been shown to mediate the inhibition of metastasis by CCL2-transduced human lung adenocarcinoma cells in the SCID mouse model [99 ].


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CONCLUDING REMARKS
 
Chemokines have been shown to play a central role in the migration and trafficking of T and B lymphocytes in vivo [22 23 24 25 26 27 ]. It is likely that chemokines have a similar role in the biology of NK cells. Differential expression of chemokine receptors [30 ] and adhesion molecules [30 , 100 , 101 ] by CD56bright and CD56dim human NK cells suggests that these subsets may home to different microenvironments in vivo [14 ]. Indeed, expression of CCR7 and high levels of L-selectin by resting CD56bright NK cells [11 , 30 , 100 ] should direct them to secondary lymphoid tissues [30 , 41 , 100 101 102 103 ]. Because CD56bright NK cells produce large quantities of IFN-{gamma} and other cytokines after activation [11 , 16 , 62 ], it is also reasonable to hypothesize that they can regulate adaptive T- and B-cell responses in secondary lymphoid tissues. In contrast, resting CD56dim NK cells do not express CCR7 and express little or no L-selectin [11 , 30 , 100 ]; however, they express high levels of LFA-1 and other adhesion molecules [17 , 30 , 40 , 100 ]. Thus, CD56dim NK cells are expected to migrate to peripheral nonlymphoid tissues rather than secondary lymphoid organs. However, CD56dim NK cells express CCR7 after activation [40 ], which could promote their migration to regional lymph nodes after they have been stimulated at sites of inflammation in peripheral tissues. Chemokines can also affect the cytolytic activity and proliferation of NK cells, potentially indicating a major role for chemokines in the regulation of NK cell responses to tumors and infectious pathogens. Further investigation is required to dissect the contribution of chemokines to the migration and effector function of NK cells in vivo. Such studies will further our understanding of basic NK cell biology and may facilitate the manipulation of NK cells in the treatment of human infectious and neoplastic diseases.


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ACKNOWLEDGEMENTS
 
The author is supported in part by a National Institutes of Health grant 3MO1 RR00750-27S3. I am grateful to Barrett Rollins, M.D., Ph.D., Hal Broxmeyer, Ph.D., and Robert Hromas, M.D., for providing helpful comments and suggestions.

Received November 1, 2001; revised November 29, 2001; accepted November 30, 2001.


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