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

doi:10.1038/ncomms9266

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 journal › Article › peer-review

87 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 language	English (US)
Article number	8266
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9266
State	Published - Sep 14 2015

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "GITR subverts Foxp3 + Tregs to boost Th9 immunity through regulation of histone acetylation",

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.",

author = "Xiang Xiao and Xiaomin Shi and Yihui Fan and Xiaolong Zhang and Minhao Wu and Peixiang Lan and Laurie Minze and Fu, {Yang Xin} and Ghobrial, {Rafik M.} and Wentao Liu and Li, {Xian Chang}",

year = "2015",

month = sep,

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doi = "10.1038/ncomms9266",

language = "English (US)",

volume = "6",

journal = "Nature communications",

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T1 - GITR subverts Foxp3 + Tregs to boost Th9 immunity through regulation of histone acetylation

AU - Xiao, Xiang

AU - Shi, Xiaomin

AU - Fan, Yihui

AU - Zhang, Xiaolong

AU - Wu, Minhao

AU - Lan, Peixiang

AU - Minze, Laurie

AU - Fu, Yang Xin

AU - Ghobrial, Rafik M.

AU - Liu, Wentao

AU - Li, Xian Chang

PY - 2015/9/14

Y1 - 2015/9/14

N2 - 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.

AB - 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.

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

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