Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Abstract

Human CMV (HCMV) infection promotes a variable and persistent expansion of functionally mature NKG2Cbright NK cells. We analyzed NKG2Cbright 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-α and IFN-γ) 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 NKG2Cbright NK cells was FcεR γ-chain defective and highly responsive to Ab-driven activation, being particularly efficient in the production of antiviral cytokines, mainly TNF-α. Remarkably, the expansion of NKG2Cbright NK cells in HCMV+ subjects was related to the overall magnitude of TNF-α and IFN-γ 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 NKG2Cbright NK-cell subset. Furthermore, we disclose the proinflammatory potential of NKG2Cbright NK cells, a variable that could influence the individual responses to other pathogens and tumors.