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, Xian Chang Li

Research output: Contribution to journalArticle

55 Scopus citations

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-? B 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.

Original languageEnglish (US)
Article number8266
JournalNature Communications
Volume6
DOIs
StatePublished - Sep 14 2015

    Fingerprint

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Xiao, X., Shi, X., Fan, Y., Zhang, X., Wu, M., Lan, P., Minze, L., Fu, Y. X., Ghobrial, R. M., Liu, W., & Li, X. C. (2015). GITR subverts Foxp3 + Tregs to boost Th9 immunity through regulation of histone acetylation. Nature Communications, 6, [8266]. https://doi.org/10.1038/ncomms9266