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

AM Beal, N Ramos-Hernández, CR Riling… - Nature …, 2012 - nature.com
AM Beal, N Ramos-Hernández, CR Riling, EA Nowelsky, PM Oliver
Nature immunology, 2012nature.com
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 …
Abstract
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.
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