TNFα Augments Cytokine-Induced NK Cell IFNγ Production through TNFR2

Abstract

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

Chlamydia psittaci -Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

“…This pathway appears to operate through both TNFR1 and TNFR2 (Fig. 4), which both play a crucial role in the activation of IFN-␥ production by NK cells (20,66). The activation of NK cells can also be mediated via soluble TNF-␣ released by monocytes, macrophages, and/or DCs (66).…”

“…4), which both play a crucial role in the activation of IFN-␥ production by NK cells (20,66). The activation of NK cells can also be mediated via soluble TNF-␣ released by monocytes, macrophages, and/or DCs (66). However, the advantage of exosome-mediated activation could be the combined effects of various membrane-bound factors/ligands (23), potentially leading to a more effective NK cell response.…”

TNFR2/BIRC3-TRAF1 signaling pathway as a novel NK cell immune checkpoint in cancer

“…The prevailing conundrum is that TNFa augments cytokine-induced NK cell IFNg production through TNFR2 46 which is supported by the decreased activation of NK cells observed in patients exposed to anti-TNF Abs. 47 This TNFainduced NK cell activation can culminate in apoptotic NK cell death as reported in pioneering reports exposing NK cells to IL-2/IL-12.…”

Natural killer cell activation contributes to hepatitis B viral control in a mouse model

“…IL-12 has been reported to be involved in promoting NK cell accumulation in the liver 28 . TNF-α, another cytokine released mainly by activated macrophages, could also recruit NK cells to liver and enhance NK cell IFN-γ production in vitro and in vivo 29 , 30 . These study may be helpful for further analysis of the mechanisms KCs use to activate NK cells in our model.…”