Transmembrane TNF–TNFR2 Antagonizes TH17 Differentiation by Promoting Il2 Expression

Abstract

Abstract While IL-17 is critical for host defense, its overabundance promotes autoimmunity. IL-2 represses TH17 differentiation, but a role for tumor necrosis factor (TNF) in this process is not well defined. TNF binds TNF receptor 1 (TNFR1) and TNFR2 to stimulate opposing signaling cascades. Whereas sTNF signals through TNFR1, tmTNF preferentially activates TNFR2. We have previously demonstrated reduced IL-2 production in TNFR1−/− TNFR2−/− double knockout CD4+ T cells. To further explore the mechanism by which TNF regulates IL-2 production, we generated TNFR1−/−, TNFR2−/−, and TNFR1−/− TNFR2−/− 5C.C7 TCR Il2-GFP mice to study Il2 transcription at the single cell level. Our findings indicate that CD4+ T cell–intrinsic tmTNF/TNFR2 stimulates Il2 promoter activity and Il2 mRNA stability. Pharmacological blockade of TNF in wild-type C57BL/6 mice and tmTNF Foxp3-GFP mice also demonstrated tmTNF/TNFR2-mediated augmentation of Il2 expression. We further report elevated expression of TNFR2 on the surface of TH17-polarized CD4+ T cells and show that tmTNF/TNFR2, but not sTNF/TNFR1, inhibits TH17 differentiation. Under TH17-polarizing conditions, elevated IL-17 production by TNFR2-knockout CD4+ T cells correlated with increased STAT3 activity and was prevented by exogenous IL-2. We conclude that increased IL-2 production in response to CD4+ T cell–intrinsic tmTNF/TNFR2 signaling is sufficient to inhibit TH17 differentiation in a Foxp3-independent manner.