Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation

Abstract Natural killer (NK) cell function is regulated by a balance of activating and inhibitory signals. Tumor necrosis factor (TNF) is an inflammatory cytokine ubiquitous across homeostasis and disease, yet its role in regulation of NK cells remains unclear. Here, we find upregulation of the immune checkpoint protein, T cell immunoglobulin and mucin domain 3 (Tim3), is a biomarker of TNF signaling in NK cells during Salmonella Typhimurium infection. In mice with conditional deficiency of either TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2) in NK cells, we find TNFR1 limits bacterial clearance whereas TNFR2 promotes it. Mechanistically, via single cell RNA sequencing we find that both TNFR1 and TNFR2 induce the upregulation of Tim3, while TNFR1 accelerates NK cell death but TNFR2 promotes NK cell accumulation and effector function. Our study thus highlights the complex interplay of TNF-based regulation of NK cells by the two TNF receptors during inflammation.