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-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.
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Minhao
authors.initials: M
authors.lastname: Wu
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Peixiang
authors.initials: P
authors.lastname: Lan
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Minze
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.|Department of Surgery, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Rafik M
authors.initials: RM
authors.lastname: Ghobrial
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Wentao
authors.initials: W
authors.lastname: Liu
authors.affiliation: Center for Immunobiology &Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA.|Department of Surgery, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Xian Chang
authors.initials: XC
authors.lastname: Li
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology*; D006657:Histones / Q000378:metabolism*; D015151:Immunoblotting; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006657:Histones; D052002:NF-kappa B p50 Subunit; D050800:STAT6 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C498833:Foxp3 protein, mouse; C494100:Stat6 protein, mouse; C106544:Tnfrsf18 protein, mouse; C073701:Nfkb1 protein, mouse