Cutting Edge: TGF-β Induces a Regulatory Phenotype in CD4+CD25− T Cells through Foxp3 Induction and Down-Regulation of Smad7

TLDR

Regulatory T cells (CD4⁺CD25⁺) are thymically derived, yet peripheral induction mechanisms remain unclear. The study tests whether TGF‑β can induce Foxp3 and a regulatory phenotype in peripheral CD4⁺CD25⁻ T cells. TGF‑β drives Foxp3 expression in both murine and human CD4⁺CD25⁻ T cells, Foxp3 suppresses Smad7, amplifying Smad3/4 signaling and establishing a regulatory phenotype.

Abstract

Abstract CD4+CD25+ regulatory cells are a subpopulation of T lymphocytes of thymic origin. However, recent data suggest an alternative commitment of regulatory T cells in the periphery, although the precise mechanism is unknown. In the present work, we demonstrate that TGF-β is able to induce Foxp3 expression and subsequently a regulatory phenotype in CD4+CD25− peripheral murine T cells. Similarly, TGF-β induced Foxp3 in human CD4+CD25− T cells. Moreover, we show that the inhibitory Smad7 protein that is normally induced by TGF-β and limits TGF-β signaling, is strongly down-regulated by Foxp3 at the transcriptional level. Foxp3-mediated down-regulation of Smad7 subsequently rendered CD4+CD25− T cells highly susceptible to the morphogenic and regulatory effects of TGF-β signaling via Smad3/4. In summary, we demonstrate that TGF-β induces a regulatory phenotype in CD4+CD25− T cells through the induction of Foxp3 and a positive autoregulatory loop of TGF-β signaling due to the absence of Smad7.