Antibody-Dependent NK Cell Activation Differentially Targets EBV-Infected Cells in Lytic Cycle and Bystander B Lymphocytes Bound to Viral Antigen–Containing Particles

Abstract

NK cells have been reported to respond against EBV-infected B cells in the lytic cycle and to control the viral infection involving IFN-γ secretion. Early reports proposed a role for NK cell Ab-dependent cellular cytotoxicity (ADCC) triggered via FcγR-IIIA (CD16) in the response to EBV. In the current study, we revisited this issue, showing that serum from EBV individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-α and IFN-γ) against EBV-infected cells, enhancing NK cell activation. The effect was preferentially directed against cells in the lytic phase and was associated with surface expression of the gp350/220 envelope Ag. In contrast, binding of gp350 particles, released by EBV-infected cells, to B cell lines or autologous primary B lymphocytes also promoted specific Ab-dependent NK cell degranulation and TNF-α production but induced minimal IFN-γ secretion. In that case, target cell damage appeared marginal compared with the effect of a control anti-CD20 Ab (rituximab) at concentrations that triggered similar NK cell activation, indicating that cell-associated gp350 particles may divert the cytolytic machinery, impairing its direct action on the plasma membrane. These observations support that Ab-dependent NK cell activation plays an important role in the control of EBV, enhancing NK cell effector functions against infected B cells in the lytic cycle. In contrast, the data reveal that gp350 particles bound to bystander B cells trigger Ab-dependent NK cell degranulation and TNF-α but not cytotoxicity or IFN-γ production, potentially favoring the progression of viral infection.

Low cytomegalovirus seroprevalence in early multiple sclerosis: a case for the ‘hygiene hypothesis’?

“…In addition, CMV may induce an adaptive differentiation and persistent expansion of an NKG2C+ natural killer (NK)‐cell subset , and this effect has been recently associated with decreased MS progression . Herpesvirus coinfections might have additional immunological implications that influence the responses against other pathogens . In this study, we evaluated whether CMV infection and its imprint on the T‐cell and NK‐cell compartments may differ in early MS as compared with patients with non‐early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against EBV and HHV‐6.…”

Natural killer cell activation by respiratory syncytial virus‐specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc‐glycosylation

“…17 In addition, antibody-dependent activation of NK cells is known to result in the secretion of pro-inflammatory cytokines, including interferon-gamma (IFN-c). 18 Several groups have shown clearance of RSVinfected cells by peripheral blood mononuclear cells (PBMCs) in the presence of monoclonal antibodies, or antibodies from different natural sources, including breastmilk, cord blood, nasopharyngeal secretions and serum. [19][20][21][22][23] However, none of these studies shows whether killing was specifically NK cell-mediated.…”

“…Engagement of the main NK cell Fc gamma receptor (FcγRIIIa) by antibodies bound to virus‐infected cells leads to the release of cytotoxic granules containing perforins and granzymes, a process known as antibody‐dependent cell‐mediated cytotoxicity (ADCC) . In addition, antibody‐dependent activation of NK cells is known to result in the secretion of pro‐inflammatory cytokines, including interferon‐gamma (IFN‐γ) …”

High Numbers of Circulating CD57+ NK Cells Associate with Resistance to HER2-Specific Therapeutic Antibodies in HER2+ Primary Breast Cancer

“…Genetic (i.e., KIR and HLA haplotypes) and environmental factors, including infection by human cytomegalovirus (HCMV), respectively, shape the steady-state distribution of the NK-cell receptor repertoire and the development of circulating NK-cell subsets with adaptive features (14)(15)(16)(17). HCMVinduced adaptive NK cells, identified by elevated expression of the activating receptor CD94/NKG2C, among other phenotypic and epigenetic features, display enhanced ADCC responses in several in vitro experimental models (18)(19)(20). Biological age is another factor associated with changes in the composition of the human NK-cell repertoire (21,22).…”