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

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.

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

“…Studies have reported that TGF-has the ability to induce CD4 + CD25 -cells to become CD4 + CD25 + Tregs in vitro [52,53], and TGF-can induce FoxP3 expression in iTregs [54,55]. Additionally, other studies have clearly demonstrated that the suppressive capacity of FoxP3 + Tregs in vivo is via a TGF--dependent mechanism [56,57].…”

Is FOXP3 a bona fide marker for human regulatory T cells?

“…As mentioned earlier, the initial studies indicating that FOXP3 was exclusively expressed in human nTreg [9,10] have been disputed by recent works that identified transient FOXP3 expression in activated human CD4 + CD25 -T effector (Teff) cells in the presence or absence of TGF-b [9,[11][12][13][14][15][16][17]. Notably, the resulting FOXP3-expressing T cells can either exert suppressive functions [9,11,13,15,18] or not [12,14,[16][17][18].…”

“…Notably, the resulting FOXP3-expressing T cells can either exert suppressive functions [9,11,13,15,18] or not [12,14,[16][17][18]. Stimulation via TCR of Teff cells, which results in transient FOXP3 expression [16,17], does not confer suppressive activity.…”

In vitro generation of CD4+CD25+ regulatory cells from murine naive T cells

“…We and others have recently shown that cells endowed with regulatory capacity comparable to that of naturally occurring Tregs might be obtained upon activation of naive T cells in the presence of the cytokine TGF-b 8,9 . This protocol describes the methods used in these papers in more detail.…”