Abstract
Abstract TGF-ß induces the development of Foxp3+ regulatory T (iTreg) and IL-17-producing (Th17) cells based on the present cytokines. However, the signaling pathways involved in the differentiation of these cells are poorly defined. TGF-ß signals through Smad-dependent and -independent pathways to affect T cell responses. While others reported Smad3 is required for activity of the Foxp3 enhancer, our studies suggest that Smad3 is not essential for TGF-ß to induce Foxp3+ expression. In naïve CD4+CD25- cells isolated from either Smad3 KO or Smad2 conditional KO mice, TGF-ß was still able to induce TCR-activated T cells to express Foxp3 and developed suppressive activity, although the level of Foxp3 was slightly lower than induction in wild type cells. TGF-ß induced naïve CD4+ cells from wild type and Smad3-/- CD4+ to become Th17 cells in the presence of IL-6. Addition of retinoic acid (ATRA) increased iTreg differentiation and controlled Th17 development in both wild type and Smad3-/- mice. These results suggest that although the combined effects of Smad2 and Smad3 may be needed for the induction of iTreg and Th17 cells, Smad-independent signaling pathways are also required for these TGF-ß differentiation effects. (Supported by ACR REF Award and Outstanding youth Scientist Award from NSFC)
Published Version
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