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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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Cell Differentiation / immunology
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Chromatin Immunoprecipitation
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Electrophoresis, Polyacrylamide Gel
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Flow Cytometry
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Forkhead Transcription Factors / immunology
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Glucocorticoid-Induced TNFR-Related Protein / immunology*
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Histones / metabolism*
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Immunoblotting
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Melanoma, Experimental / immunology*
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Mice
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NF-kappa B p50 Subunit / metabolism
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Phenotype
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Reverse Transcriptase Polymerase Chain Reaction
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STAT6 Transcription Factor
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T-Lymphocyte Subsets / immunology*
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Regulatory / immunology*
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Up-Regulation
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p300-CBP Transcription Factors / metabolism*
Substances
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Glucocorticoid-Induced TNFR-Related Protein
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Histones
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NF-kappa B p50 Subunit
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Tnfrsf18 protein, mouse
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Nfkb1 protein, mouse
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p300-CBP Transcription Factors
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p300-CBP-associated factor