Antibody-Mediated Response of NKG2C NK Cells against Human Cytomegalovirus

Human CMV (HCMV) infection promotes a variable and persistent expansion of functionally mature NKG2C bright NK cells. We analyzed NKG2C bright NK cell responses triggered by Abs from HCMV + sera against HCMV-infected MRC5 fibroblasts. Specific Abs promoted the degranulation (i.e., CD107a expression) and the production of cytokines (TNF-a and IFN-g) by a significant fraction of NK cells, exceeding the low natural cytotoxicity against HCMV-infected targets. NK cell–mediated Ab-dependent cell-mediated cytotoxicity was limited by viral Ag availability and HLA class I expression on infected cells early postinfection and increased at late stages, overcoming viral immunoevasion strategies. Moreover, the presence of specific IgG triggered the activation of NK cells against Ab-opsonized cell-free HCMV virions. As compared with NKG2A + NK cells, a significant proportion of NKG2C bright NK cells was Fc«R g-chain defective and highly responsive to Ab-driven activation, being particularly efficient in the production of antiviral cytokines, mainly TNF-a. Remarkably, the expansion of NKG2C bright NK cells in HCMV + subjects was related to the overall magnitude of TNF-a and IFN-g cytokine secretion upon Ab-dependent and-independent activation. We show the power and sensitivity of the anti-HCMV response resulting from the cooperation between specific Abs and the NKG2C bright NK-cell subset. Furthermore, we disclose the proinflammatory potential of NKG2C bright NK cells, a variable that could influence the individual responses to other pathogens and tumors. H uman CMV (HCMV) is a b-herpesvirus that infects 40– 100% of adult populations worldwide, depending on socioeconomic factors (1). In most immunocompetent individuals, primary infection is clinically silent and the virus establishes a chronic infection alternating cycles of latency and subclinical reactivations. However, immunocompromised hosts (i.e., hematopoietic and organ transplant recipients, AIDS patients) are at risk for development of severe HCMV disease. HCMV is the leading cause of congenital infection in the developed world, and can result in mental retardation and deafness (2–4). In addition, HCMV has been related to the development of atherosclerosis and immunosenescence (5, 6). Control of HCMV involves multiple immune resources, with a prominent role for IFNs, and the combined action of NK cells, T cells, and Abs. NK cells are cytotoxic lymphocytes capable of killing virus-infected cells without prior sensitization. They also secrete cytokines (i.e., IFN-g, TNF-a), which mediate a noncytolytic control of the virus, contributing to induce Th1 protective-specific responses (7, 8). Activation of NK cells is tightly controlled by the balance between inhibitory and activating receptors (9). Among …