Role of chemokines in the biology of natural killer cells

Natural killer (NK) cells participate in innate and adaptive immuneresponses to obligate intracellular pathogens and malignant tumors. Twomajor NK cell subsets have been identified in humans:CD56dim CD16+ and CD56bright CD16−. RestingCD56dim CD16+ NK cells express CXCR1, CXCR2, CXCR3, CXCR4,and CX3CR1 but no detectable levels of CC chemokine receptors on thecell surface. They migrate vigorously in response to CXCL12 and CXC3L1.In contrast, resting CD56bright CD16− NK cells expresslittle CXCR1, CXCR2, and CXC3R1 but high levels of CCR5 and CCR7. Chemotaxis of CD56bright CD16− NK cells is stimulated mostpotently by CCL19, CCL21, CXCL10, CXCL11, and CXCL12. Followingactivation, NK cells can migrate in response to additional CC and CXCchemokines. 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, andCXCL8. Chemokines secreted by NK cells may recruit other effector cellsduring immune responses. Furthermore, CCL3, CCL4, and CCL5 produced byNK cells can inhibit in vitro replication of HIV. CCL3 and CXL10expression appear to be required for protective NK cell responses invivo to murine cytomegalovirus or Leishmania major,respectively. Moreover, NK cells participate in the in vivo rejectionof transduced tumor cells that produce CCL19 or CCL21. Thus, chemokinesappear to play an important role in afferent and efferent NK cellresponses to infected and neoplastic cells.