TNFα Augments Cytokine-Induced NK Cell IFNγ Production through TNFR2

NK cells play a central role in innate immunity, acting directly through cell-mediated cytotoxicity and by secreting cytokines. TNF alpha activation of TNFR2 enhances NK cell cytotoxicity, but its effects on the other essential function of NK cells cytokine production, for which IFN gamma is paramount are poorly defined. We identify the expression of both TNF alpha receptors on human peripheral blood NK cells (TNFR2 > TNFR1) and show that TNF alpha significantly augments IFN gamma production from IL-2-/IL-12-treated NK cells in vitro, an effect mimicked by a TNFR2 agonistic antibody. TNF alpha also enhanced murine NK cell IFN gamma production via TNFR2 in vitro. In a mouse model characterized by the hepatic recruitment and activation of NK cells, TNFR2 also regulated NK cell IFN gamma production in vivo. Specifically, in this model, after activation of an innate immune response, hepatic numbers of TNFR2-expressing and IFN gamma-producing NK cells were both significantly increased; however, the frequency of IFN gamma-producing hepatic NK cells was significantly reduced in TNFR2-deficient mice. We delineate an important role for TNF alpha, acting through TNFR2, in augmenting cytokine-induced NK cell IFN gamma production in vivo and in vitro, an effect with significant potential implications for the regulation of innate and adaptive immune responses. (C) 2016 S. Karger AG, Basel