Chemokine Regulation Of Homing Within Natural Killer Cell Mediated Immunity

Natural killer (NK) cells are lymphoid-lineage cells that regulate innate immunity, primarily against tumour cells or virus infected host cells. Phenotypically, NK cells are defined by their surface expression of CD56 and lack of CD3 [67]. Approximately 90% of human NK cells in the periphery exhibit a CD56dimCD 16 (FcyRIII)hi phenotype, while the remainder are CD56bri8lllCD16 /low [68]. Functional studies based on this phenotypic dichotomy have indicated that CD56dimCD 16hi are more efficient at cytotoxic killing, while the CD56 blighlCD 16"ow subset is more apt to produce immunoregulatory cytokines [68,69], It is important to note that although mice have NK cells that function in a capacity analogous to those in humans, a murine counterpart to CD56 has not been reported, therefore, studies defining the two subsets have been limited to in vitro human studies [69],

NK cells act in a crucial capacity in the defence against select cytopathic viruses and intracellular pathogens [70], NK cells are potent producers of interferon (IFN)-y in mice, and represent the earliest and largest source of IFN-y in response to murine cytomegalovirus (MCMV) infection and inoculation with LPS [71], Via CD16, NK cells are capable of recognizing IgG immune complexes. NK cells are also capable of modulating the effector activity of monocytes, neutrophils and T and B cells via their production of cytokines and chemokines [67],

The molecular basis by which the cytotoxic activity of NK cells is activated has recently begun to be elucidated. Unlike its lymphoid counterparts, T and B cells, NK cells do not have a dominant, antigen specific receptor complex, nor do they require prior immunization or expression of autologous MHC molecules on target cells [71]. Activation of NK cytotoxicity is subject to the balance of signals of several different inhibitory and activating receptors. Insufficient expression of self-MHC, as frequently occurs in tumour or virus-infected cells, can provide an activating signal for NK cytolysis [69], NK cell activation via HLA recognition has been the best characterized mechanism; however, there are alternate routes: NKG2D, a recently characterized activating NKR, is specific for MICA, MICB or ULBP proteins, typically induced in response to cell stress [72], For reviews of NKRs and their activation pathways see Moretta et al. [71] or Cooper et al. [69], In adult humans, NK cell development occurs within the bone marrow (for a comprehensive review on NK cell development see Colucci et al. [73]). Within the periphery, NK cells have been observed in the blood, in all lymphoid tissues and to a lesser extent within the liver and spleen [73], Evidence has demonstrated that NK cells can migrate between compartments during disease or in response to inflammatory conditions [74], However, the mechanisms by which NK cells recirculate during homeostatic conditions have not been determined. Several classes of molecules have been demonstrated to regulate NK cell migration: the neurotransmitters substance P and norepinephrine are able to increase or decrease NK chemokinesis in vitro, respectively [75], Recent work has also demonstrated that a family of heptahelical receptors specific for various phospholipids can also regulate NK trafficking [76], The role of chemokines and their receptors, however, has been the most closely studied.

The cell surface repertoire of chemokine receptors on NK cells has been comprehensively studied. Because NK cells are a heterogeneous population and change their receptor profile after activation, in some cases data within the literature is conflicting. Resting NK cells appear to have expression of CCR7, CXCR3, CXCR4 and XCR1 [77-79], The expression of CCR7, however, has been reported to be only on CD56bl'ehtCD16"ow cells [77,78], The expression of CCR1, CCR4, CXCR1, CXCR2 and CX3CR1 has also been reported, however contradictory data exists [74,80], The reported expression of CXCR3, CXCR4 and XCR1 is supported by the observations that resting NK cells can migrate in response to CXCL10/IP-10, CXCL11/I-TAC or CXCL12/SDF-1 (CXCR3 and CXCR4 ligands respectively) [77-81], Although CXCR1 and CXCR2 expression has been reported by several groups, data is also contradictory on the ability of resting cells to traffic in response to CXCL1 or CXCL8. Treatment of resting NK cells with the chemokines CCL2/MCP-1 (CCR2 and CCR4), CCL3/MIP-la (CCR1, CCR4, CCR5), CCL4/MIP-1 p (CCR5), CCL5/RANTES (CCR1, CCR2, CCR4, CCR5), CCL7/MCP-3 (CCR1) and CCL8/MCP-2 (CCR1, CCR2, CCR3) has been able to elicit chemotaxis, providing support for the expression of CCR1, and, paradoxically, for the presence of CCR5 on resting cells

[77,82-84], In response to IL-2 or IL-15, activated NK cells have been demonstrated to upregu-late expression of CCR2, CCR4, CCR5 and CXCR1. Some of the disagreement in the literature surrounding the expression of these receptors on resting cells has been proposed to be due to aberrant in vitro activation.

The role of chemokine controlled migration within innate NK cell immunity has been elegantly demonstrated using in vivo models. Mice infected with MCMV exhibit early activation of NK cells with a concurrent induction of IFN-y production [85], When challenged with MCMV, mice deficient in CCL3/MIP-la demonstrate marked decreases in the NK cell trafficking to the liver and localized liver production of IFN-y. CCU/MIP-la' mice typically succumb to MCMV infection, in contrast to wild-type mice that can clear the virus. Treatment of wild-type mice with anti-CCL3/MIP-la antibodies typically diminishes the accumulation of NK cells in the liver. IFN-y levels in the serum are equivalent between knock-out and wild type mice, implying that it is the localized expression provided by the NK cells that is the controlling factor.

A second model takes advantage of the differential ability of strains with polarized Thl/Th2 responses to combat infection by the obligate intracellular pathogen Leishmania major. C57BL/ 6 mice develop a Thl response and efficiently combat L. major infection, whereas the Balb/c strain is polarized to a Th2 response and typically succumb [86-88], NK cells within draining lymph nodes in Balb/c mice demonstrate lower cytotoxic responses and level of activation compared to C57BL/6 mice [86], Expression of XCLl/lymphotactin a, CCL2/MCP-1 and CXCL10/ interferon-gamma-inducible protein-10 (IP-10) within draining lymph nodes could be detected within resistant mice during acute infection, but was absent in susceptible mice [86], Injection of CXCL10/IP-10 at the site of infection improved NK cell cytotoxicity within the lymph nodes of Balb/c mice, however, no difference in the numbers of NK cells were detected between strains [86], Therefore, it is unclear whether CXCL10/IP-10 is acting to augment NK migration within the lymph node architecture, or provide a stimulatory signal directly.

Several models of tumourigenesis have also demonstrated the role of chemokines in regulating NK mediated immunity. Transgene expression of CCL19/MIP-3|3 or CCL7/MCP-3 in murine breast or lung tumour-inducing cell lines, respectively, was able to reduce tumour survival in vivo and was correlated with recruitment of NK cells [89,90]. Mice deficient in CCR1 have defective recruitment of NK cells to granulomatous lesions and demonstrated decreased IFN-y production [91].

The data from in vivo models of infectious disease and cancer provide convincing evidence that the migration of NK cells is crucial to their function. Based on the literature to date, it remains a reasonable hypothesis that the primary function of the inflammatory chemokine receptors on NK cells is to enable recruitment to primary sites of infection/tumourigenesis. Mature NK cells also express the homeostatic receptors CXCR4 and CCR7. These receptors may allow NK cells to localize to specific regions within secondary lymphoid organs to act as regulatory cells. Alternatively, CXCR4 expression has also been proposed to regulate the ability of NK cells to traffic to the bone marrow. Compared to the other major leukocyte subsets, the models describing chemokine regulation of NK cell migration are rather undeveloped. Further work in this burgeoning field will undoubtedly uncover novel aspects of NK cell biology and expand our understanding of their role in immunity as a whole.

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