Infection Decreases Smad7 Expression in Intestinal CD4 T Cells, Which Allows TGF-β to Induce IL-10-Producing Regulatory T Cells That Block Colitis.

Helminthic infections modulate host immunity and may protect their hosts from developing immunological diseases like inflammatory bowel disease. Induction of regulatory T cells (Tregs) may be an important part of this protective process. infection also promotes the production of the regulatory cytokines TGF-β and IL-10 in the gut. In the intestines, TGF-β helps induce regulatory T cells. This study used Foxp3/IL-10 double reporter mice to investigate the effect of TGF-β on the differentiation of colon and mesenteric lymph node-derived murine Foxp3 IL-10 CD4 T cells into their regulatory phenotypes. Foxp3 IL-10 CD4 T cells from -infected mice, as opposed to T cells from uninfected animals, cultured in vitro with TGF-β and anti-CD3/CD28 mAb differentiated into Foxp3 and/or IL-10 T cells. The IL-10-producing T cells nearly all displayed CD25. Smad7 is a natural inhibitor of TGF-β signaling. In contrast to gut T cells from uninfected mice, Foxp3 IL10 CD4 T cells from -infected mice displayed reduced Smad7 expression and responded to TGF-β with Smad2/3 phosphorylation. The TGF-β-induced Tregs that express IL-10 blocked colitis when transferred into the Rag/CD25 CD4 T cell transfer model of inflammatory bowel disease. TGF-β had a greatly diminished capacity to induce Tregs in -infected transgenic mice with constitutively high T cell-specific Smad7 expression. Thus, infection with causes down-modulation in Smad7 expression in intestinal CD4 T cells, which allows the TGF-β produced in response to the infection to induce the Tregs that prevent colitis.