Critical role for the chemokine receptor CXCR 6 in NK cell – mediated antigen-specific memory of haptens and viruses

The textbook view of adaptive immunity is that it is mediated exclusively by T cells and B cells, which rely on nonhomologous recombination of variable, diversity and joining gene segments mediated by the RAG-1–RAG-2 recombinase to generate a diverse repertoire of T cell and B cell antigen receptors1. The activation of such receptors by cognate antigen triggers clonal selection and differentiation into short-lived effector cells and long-lived memory cells that, after antigen rechallenge, mount accelerated and enhanced recall responses. Classic examples of such antigen-specific memory, the hallmark of adaptive immunity, include delayed-type hypersensitivity (DTH)2,3 and hapten-induced contact hypersensitivity (CHS)4,5. Like T cells and B cells, natural killer (NK) cells mediate resistance to tumors and infections by a variety of mechanisms that are still incompletely understood6. However, NK cells cannot express RAG-dependent receptors and instead use germline-encoded receptors that integrate activating and dampening signals7. Notable examples of mouse NK cell receptors that detect specific pathogen–associated structures include NKp46 and Ly49H, which recognize influenza A–encoded hemagglutinin (HA)8,9 and the murine cytomegalovirus (MCMV)-encoded m157 protein10, respectively. Mouse NK cells can express just one Ly49 receptor or random combinations of several Ly49 receptors, some of which recognize host major histocompatibility complex (MHC) class I (refs.11,12). Ly49H is a member of this family and confers NK cell– mediated resistance to MCMV infection in C57BL/6 mice. Notably, Ly49H+ NK cells develop features of adaptive immunity after infection with this virus13. However, as Ly49H is found only in the C57BL/6 strain14, it has been unclear whether NK cells can develop virus-specific memory in other genetic backgrounds or in response to viruses other than MCMV. This question may also be clinically relevant, as certain NK cell subsets have been linked to the ability of rare people infected with human immunodeficiency virus type 1 (HIV-1) to exert long-term control over HIV-1 replication15,16. The idea that NK cells can mediate adaptive immunity was initially suggested by observations that mouse strains that lack T cells and B cells develop vigorous CHS responses to various distinct haptens17,18. These responses have the hallmarks of adaptive immunity: they are sensitization dependent, persist for at least 4 weeks and are elicited only by haptens to which mice have previously been sensitized17. Several lines of evidence have established that NK cells are necessary and sufficient for this activity: CHS responses in mice deficient in recombination-activating gene 2 (Rag2−/− mice) are abolished after depletion of NK cells and are absent from Rag2−/− mice also deficient in the gene encoding the γ-chain of the interleukin 2 (IL-2) receptor (Il2rg−/− mice), which lack all lymphocytes, including NK cells19. Moreover, after sensitization of donor mice with 2,4dinitro-1-fluorobenzene (DNFB), adoptive transfer of NK cells from donor livers confers vigorous CHS to naive Rag2−/−Il2rg−/− recipient mice but adoptive transfer of NK cells from spleens does not. Among hepatic NK cells, DNFB-specific memory is concentrated in a subset expressing Thy-1 and Ly49C/I17. However, those and all other NK