Control of the differentiation of regulatory T cells and TH17 cells by the DNA-binding inhibitor Id3
نویسندگان
چکیده
Regulatory T cells (Treg cells) that express the transcription factor Foxp3 are instrumental in the induction and maintenance of peripheral immune tolerance and the regulation of tumor immunity and infection1–8. The differentiation of Foxp3+ Treg cells requires transforming growth factor-β (TGF-β) signaling9–13; however, the molecular pathways that transduce this signal remain largely unknown. The TGF-β receptor–regulated adaptor molecules Smad2 and Smad3 and the common Smad protein Smad4 are involved in Foxp3 induction14–16. However, the Foxp3 promoter lacks Smad-binding sequences. In addition, the time lag between the activation of Smad2 or Smad3 (within minutes) and Foxp3 mRNA expression (over 12 hours) after stimulation with TGF-β1 suggests that there are intermediate factors between the TGF-β1mediated Smad signaling and Foxp3 transcription. Thus, understanding this is not only essential for understanding the generation of Treg cells but also important for the treatment of autoimmune diseases, infection and cancer17, especially given the reciprocal differentiation of TGF-β1-induced Foxp3+ Treg cells and interleukin 17 (IL-17)-producing helper T cells (TH17 cells)18–23. Here we here show that the DNA-binding inhibitor Id3, a transcription factor involved in T cell development24,25, growth inhibition of a B cell progenitors26 and protection of mice against autoimmunelike Sjögren’s syndrome27, regulated the TGF-β1-mediated reciprocal differentiation of Treg cells and TH17 cells in mice. Deletion of Id3 blocked the TGF-β1-induced generation of Foxp3+ Treg cells. This was attributed to a failure to enrich binding of the transcription factor E2A and an inability to suppress binding of the transcription factor GATA3 at the Foxp3 promoter in Id3−/− T cells. These Id3−/− T cells showed more differentiation into TH17 cells in vitro and in vivo. Id3-dependent reciprocal regulation of Treg cells and TH17 differentiation also occurred in an experimental model of house dust mite (HDM)induced allergic asthma in mice.
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