Abstract
Development of Foxp3(+) regulatory T cells and pro-inflammatory Th17 cells from naive CD4(+) T cells requires transforming growth factor-β (TGF-β) signaling. Although Smad4 and Smad3 have been previously shown to regulate Treg cell induction by TGF-β, they are not required in the development of Th17 cells. Thus, how TGF-β regulates Th17 cell differentiation remains unclear. In this study, we found that TGF-β-induced Foxp3 expression was significantly reduced in the absence of Smad2. More importantly, Smad2 deficiency led to reduced Th17 differentiation in vitro and in vivo. In the experimental autoimmune encephalomyelitis model, Smad2 deficiency in T cells significantly ameliorated disease severity and reduced generation of Th17 cells. Furthermore, we found that Smad2 associated with retinoid acid receptor-related orphan receptor-γt (RORγt) and enhanced RORγt-induced Th17 cell generation. These results demonstrate that Smad2 positively regulates the generation of inflammatory Th17 cells.
Highlights
TGF-, signaling through a heteromeric TGFRII and TGFRI complex, activates the phosphorylation of Smad2 and Smad3, which associate with the common partner Smad4, and translocate to the nucleus [4]
We found that Smad2 associated with retinoid acid receptor-related orphan receptor-␥t (ROR␥t) and enhanced ROR␥t-induced Th17 cell generation
We have previously shown that TGF- signaling through TGFRI is required for generation of both Th17 and iTreg cells [5]
Summary
TGF-, signaling through a heteromeric TGFRII and TGFRI complex, activates the phosphorylation of Smad2 and Smad3, which associate with the common partner Smad4, and translocate to the nucleus [4]. Smad2 Deficiency Leads to a Partial Reduction in TGF-induced Foxp3 Expression—To address the role of Smad2 in T cell differentiation, Smad2 floxed mice [7] were crossed with CD4-Cre transgenic mice [8] to generate mice lacking Smad2 in T cells (Smad2 tKO), which results in the absence of Smad2 but not Smad3 protein in CD4ϩ and CD8ϩ T cells but not in B cells (supplemental Fig. 1).
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