Natural killer cells might adapt their inhibitory receptors for memory

Traditional teaching in immunology tells us that antigen-specific recall responses are the realm of adaptive immunity. However, over the past decade, there has been increasing evidence and interest in the concept of innate immune memory. Natural killer (NK) cells are the founding member of the innate lymphocyte family, initially recognized more than 40 y ago for their ability to kill tumor targets without prior sensitization across MHC haplotypes. Since that time, germline-encoded NK cell receptors (NKRs) that recognize class I MHC (MHC-I) molecules and deliver “activating” or “inhibitory” signals dictating NK cell education and function have been found. A decade ago, NK cells were discovered to have the capacity for specific recall responses to diverse antigens, akin to those seen in T cells. The mechanism by which NK cells specifically recognize a wide range of antigens is unknown. In PNAS, Wight et al. (1) provide evidence that inhibitory NKRs might recognize antigen in the context of MHC-I molecules to mediate NK cell memory responses. The first evidence for NK cell memory responses came when O’Leary et al. (2) demonstrated that a subset of liver NK cells mediates hapten-specific contact hypersensitivity (CHS) in Rag-deficient mice. Adoptive transfer experiments of purified NK cells demonstrated specificity of long-lived NK cell recall responses (2, 3). Three major types of NK cell memory or memory-like responses are now recognized: antigen-specific responses, CMV-adapted memory (in the mouse reliant on a virally encoded ligand interacting with a germline-encoded NK cell-activating receptor), and cytokine-induced antigen-independent memory-like responses (2, 4⇓⇓–7). Wight et al. (1) focus on antigen-specific NK cell memory and investigate whether Ly49 inhibitory NKRs can recognize antigen. Antigen-specific NK cell memory has been demonstrated for a wide variety of antigens, including haptens, viral-like particles, and in the context of infections such … ↵11Email: cooperₘatwustl. edu. 1: #xref-corresp-1-1