1. Regulation of regulatory T cell fate by nuclear factors and epigenetics
Feb. 24(WED), 11:00 / Auditorium (1F), PBC
Akihiko Yoshimura
Keio University School of Medicine
Regulatory T cells (Tregs) play a central role in maintaining immune homeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. We have shown that Smad2 and Smad3 are redundantly essential for the induction of Foxp3 by TGF-beta in naive T cells (Takimoto et al. J. Immunol. 2010;185, 842). However, molecular mechanism for Foxp3 induction in thymic natural-occurring Treg (nTreg) cells remains to be defined. By functional screening, we identified NR4a family receptors, NR4a1, NR4a2, and NR4a3 as a strong activator of the Foxp3-promoter . Deletion of all three NR4a receptors in T cells in mice resulted in complete loss of Treg development and severe systemic autoimmunity (Sekiya et al. Nature Immunol. 2013, 14(3):230-7). We also fond that NR4a factors are essential for maintaining Foxp3 and Eos expression and also for repression of Th2 and Tfh phenotypes (Sekiya et al. J Exp Med. 2015;212(10):1623). These findings demonstrate that Nr4a controls a novel genetic program indispensable for Treg cell maintenance and function. It has been shown that epigenetic modifications, especially demethylation of CNS2 region of the Foxp3 gene enhancer, are also very important for a stable expression of Foxp3. We have shown that overexpression of Tet methylcytosine dioxygenase facilitates DNA demethylation of CNS2 and generation of functionally stable artificial Tregs.
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