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.
Highlights
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
In contrast to other T helper subsets, Th9 induction requires a constellation of transcription factors, which include SMAD2/3, PU.[1], IRF4, STAT5, STAT6, NFAT, GATA1, GATA3, Notch, as well as BATF, RelB/p52, and a single ‘master’ transcription factor has yet been identified in Th9 induction
Inhibition of Foxp[3] allows GITR to render Il9 locus accessible by activating the STAT6/p300 pathway and direct the transcriptional activities induced by iTreg-polarizing cytokines to the Il9 site to support Th9 induction
Summary
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. We demonstrate that GITR ligation subverts the induction of Foxp[3] þ Tregs and directs the activated CD4 þ T cells to Th9 cells Such GITR-mediated iTreg to Th9 induction enhances anti-tumour immunity in vivo. Naive CD4 þ T cells can differentiate into functionally distinct T helper subsets upon activation (for example, Th1, Th2, Th17, Th9), as shown by differences in the cytokines they produce[7] This process is transcriptionally regulated and involves various cytokines and costimulatory signals[8]. We examined the mechanisms of GITR costimulation in regulating fate-decisions of CD4 þ T-helper cells, and found that under iTreg-polarizing conditions, GITR ligation inhibits iTregs and selectively diverts the cells to a Th9 phenotype, which enhances anti-tumour immunity in vivo. We found that GITR signalling controls chromatin remodelling at the Foxp[3] and Il9 loci via regulation of histone acetylation and deacetylation status, and the suppression of iTregs and induction of Th9 cells
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