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

Xiang Xiao, Xiaomin Shi, Yihui Fan, Xiaolong Zhang, Minhao Wu, Peixiang Lan, Laurie Minze, Yang-Xin Fu, Rafik M. Ghobrial, Wentao Liu and Xian Chang Li ()
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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
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

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9266

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