TNFa/TNFR2 axis mediates natural killer cell proliferation by enhancing their glycolytic plasticity
Natural Killer (NK) cells are predominant innate lymphocytes that provide the early response during infection. NK cells undergo metabolic switch to fuel augmented proliferation and activation following infection. TNFa is a well-known inammatory cytokine that enhances NK cell function, however, a mechanism for stimulation is not well established. Here, we demonstrated that upon infection/inammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity and effector function. Notably, IL-18 can induce TNFR2 on NK cells, augmenting their sensitivity towards TNFa. Mechanistically, TNFa-TNFR2 signaling induces CD25 (IL-2Ra) expression on NK cells predominantly by autocrine mode, leading to a metabolic switch towards aerobic glycolysis. Accordingly, genetic ablation of TNFR2 curtails the CD25 upregulation and TNFa-induced glycolysis, leading to impaired NK cell proliferation during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFa-TNFR2 axis in NK cells for proliferation, glycolysis, and effector function via CD25 induction. Overall design: Ly49H+ natural killer (NK) cells from CD45.1-WT and CD45.2-TNFR2 knockout (KO) mice were co-transferred into NSG mice. The mice were then infected with murine cytomegalovirus (MCMV). On day 3.5 post-infection, Ly49H+ cells (CD45.1 or CD45.2) were isolated using flow sorting and analyzed using bulk RNA-seq.