During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94-NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56

During mouse cytomegalovirus (CMV) infection, a population of Ly49H ؉ natural killer (NK) cells expands and is responsible for disease clearance through the induction of a "memory NK-cell response." Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C ؉ NK cells expanded and were potent producers of IFN␥. NKG2C ؉ NK cells predominately expressed killer cell immunoglobulin-like receptor, and self-killer cell immunoglobulinlike receptors were required for robust IFN␥ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56 dim NK cells. Strikingly, increased frequencies of NKG2C ؉ NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C ؉ NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFN␥ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFN␥, T-bet, and IL-15R␣ mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation. (Blood. 2012; 119(11):2665-2674) IntroductionNatural killer (NK) cells are important effectors during the host innate immune response to viral infections. They can recognize and eliminate virally infected cells, interact with dendritic cells, and produce a range of cytokines and chemokines (eg, IFN␥, TNF-␣, MIP-1␣, MIP-1␤, and RANTES) that recruit and modulate the adaptive immune response.Under normal homeostatic conditions, a balance of activating and inhibitory signals tightly controls NK-cell function. 1,2 The best-characterized inhibitory receptors are the inhibitory killer cell immunoglobulin-like receptors (KIRs) that recognize allelic epitopes present on certain class I human leukocyte antigens (HLAs) and the C-type lectin-like receptor NKG2A, which recognizes the nonclassic class I HLA, HLA-E. 3,4 Activating signals are mediated by receptor families, including activating KIR, NKG2C, NKG2D, the natural cytotoxicity receptors (NKp30, NKp44, and NKp46), CD16, and CD244. 1 When self HLA is down-regulated, cells are susceptible to NK-cell lysis because of the lack of ligands for the inhibitory receptors, a phenomenon known as the "missing self" hypothesis. 5,6 Human cytomegalovirus (CMV), a member of the Herpesviridae family, causes asymptomatic or mild illness in healthy people. 7 CMV remains latent in infected hosts and, by adulthood, approximately 60% of people in the United States are seropositive for CMV. 8 However, for patients immunosuppressed due to HIV infection or solid organ or hematopoietic call transplantatio...

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