TGF-β renders in vivo regulatory T cell function independent of TNF-α. (117.3)

Abstract

TNF-α plays a multifunctional role in autoimmune diseases as reflected in the variable responses of different human diseases to anti-TNF-α therapy. Recent studies have suggested that TNF-α may modulate autoimmunity partially via effects on regulatory T cells (Tregs) mediated through the type II TNF receptor (TNFR2). We have now investigated the requirement for TNFR2 in both murine natural Treg (nTreg) and induced Treg (iTreg) suppression of autoimmunity. Surprisingly, we find that TNFR2 is required for nTreg but not iTreg suppression of colitis. Abnormal TNFR2-/- nTreg function was not associated with a decrease in accumulation, stability or phenotypic markers known to be relevant in Treg function. As iTregs are generated in the presence of TGF-β, we investigated whether activation in the presence of TGF-β could overcome the functional defect in TNFR2-/- nTregs. While pre-activation alone did not restore suppressive function of TNFR2-/- nTregs, pre-activation in the presence of TGF-β did. These results suggest for the first time that nTregs require TNF-α as a critical factor for activation, while iTregs replace this TNF-α requirement with TGF-β. Our findings thus not only expand on previous reports suggesting that nTregs are activated in sites of inflammation while iTregs are activated in lymph nodes, but also lend themselves to a new mechanistic understanding of the enigma of dichotomous responses to anti-TNF-α therapy in human autoimmune diseases.