TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentiation

Abstract

Induced regulatory T cells are important for peripheral tolerance. Oliver and colleagues identify a key function for the adaptor Ndfip1 in stabilizing the identity and function of such cells. Mice deficient in the adaptor Ndfip1 develop inflammation at sites of environmental antigen exposure. We show here that such mice had fewer inducible regulatory T cells (iTreg cells). In vitro, Ndfip1-deficient T cells expressed normal amounts of the transcription factor Foxp3 during the first 48 h of iTreg cell differentiation; however, this expression was not sustained. Abortive Foxp3 expression was caused by production of interleukin 4 (IL-4) by Ndfip1−/− cells. We found that Ndfip1 expression was transiently upregulated during iTreg cell differentiation in a manner dependent on transforming growth factor-β (TGF-β). Once expressed, Ndfip1 promoted degradation of the transcription factor JunB mediated by the E3 ubiquitin ligase Itch, thus preventing IL-4 production. On the basis of our data, we propose that TGF-β signaling induces Ndfip1 expression to silence IL-4 production, thus permitting iTreg cell differentiation.