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GITR subverts Foxp3+ Tregs to boost Th9 immunity through regulation of histone acetylation

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  • Xiang Xiao

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center)

  • Xiaomin Shi

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center)

  • Yihui Fan

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center)

  • Xiaolong Zhang

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center)

  • Minhao Wu

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center)

  • Peixiang Lan

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center)

  • Laurie Minze

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center)

  • Yang-Xin Fu

    (University of Chicago)

  • Rafik M. Ghobrial

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center
    Weill Cornell Medical College of Cornell University)

  • Wentao Liu

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center)

  • Xian Chang Li

    (Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center
    Weill Cornell Medical College of Cornell University)

Abstract

Glucocorticoid-induced TNFR-related protein (GITR) is a costimulatory molecule with diverse effects on effector T cells and regulatory T cells (Tregs), but the underlying mechanism remains poorly defined. Here we demonstrate that GITR ligation subverts the induction of Foxp3+ Tregs and directs the activated CD4+ T cells to Th9 cells. Such GITR-mediated iTreg to Th9 induction enhances anti-tumour immunity in vivo. Mechanistically, GITR upregulates the NF-κB family member p50, which recruits histone deacetylases to the Foxp3 locus to produce a ‘closed’ chromatin structure. Furthermore, GITR ligation also activates STAT6, and STAT6 renders Il9 locus accessible via recruitment of histone acetyltransferase p300, and together with inhibition of Foxp3, GITR induces strong Th9 responses. Thus, Th9 cells and iTregs are developmentally linked and GITR can subvert tolerogenic conditions to boost Th9 immunity.

Suggested Citation

  • Xiang Xiao & Xiaomin Shi & Yihui Fan & Xiaolong Zhang & Minhao Wu & Peixiang Lan & Laurie Minze & Yang-Xin Fu & Rafik M. Ghobrial & Wentao Liu & Xian Chang Li, 2015. "GITR subverts Foxp3+ Tregs to boost Th9 immunity through regulation of histone acetylation," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9266
    DOI: 10.1038/ncomms9266
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