TGF-β Converts Apoptotic Stimuli into the Signal for Th9 Differentiation

Abstract

Naturally arising CD4+CD25+FoxP3+ regulatory T cells (nTregs) have an essential role in maintenance of immune homeostasis and peripheral tolerance. Previously, we reported that conventional CD4+ and CD8+ T cells undergo p53-induced CD28-dependent apoptosis (PICA) when stimulated with a combination of immobilized anti-CD3 and anti-CD28 Abs, whereas nTregs expand robustly under the same conditions, suggesting that there is a differential survival mechanism against PICA between conventional T cells and nTregs. In this study, we demonstrate that TGF-β signaling is required for nTregs to survive PICA. Conversely, when an active form of exogenous TGF-β is present, conventional T cells become resistant to PICA and undergo robust expansion instead of apoptosis, with reduction of the proapoptotic protein Bim and FoxO3a. A substantial fraction of PICA-resistant T cells expressed IL-9 (TH9 cells). Moreover, the presence of IL-6 along with TGF-β led to the generation of TH17 cells from conventional T cells. Together, the data demonstrate a novel role for TGF-β in the homeostasis of regulatory T cells and effector T cell differentiation and expansion.