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.

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

“…The Th9/iTregs axis in cancer is further affected by GITR signaling (29,30). Our studies suggest that NHE1 could also be instrumental for the Th9/iTregs balance.…”

“…However, a single faithful transcription factor for Th9 cell development has not yet been described. Recent studies have also implicated glucocorticoid-induced TNFR family-related gene (GITR; gene name Tnfrsf18) signaling in Th9 cell development (29,30). Xiao et al (29) found that GITR signaling controlled chromatin remodeling at the Foxp3 and Il9 loci, and consequently was able to convert induced Tregs (iTregs) into Th9 cells.…”

“…Recent studies have also implicated glucocorticoid-induced TNFR family-related gene (GITR; gene name Tnfrsf18) signaling in Th9 cell development (29,30). Xiao et al (29) found that GITR signaling controlled chromatin remodeling at the Foxp3 and Il9 loci, and consequently was able to convert induced Tregs (iTregs) into Th9 cells. Furthermore, microRNA-15b/16 (miR-15b/16) is involved in fine tuning of iTregs/Th9 cell development thus contributing to the autoinflammation in colitis (31).…”

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

“…Although the mechanism that translates GITR ligation into an unstable nTreg phenotype is unknown, some recent studies may be relevant. Ligation of GITR inhibits induced-Treg (iTreg) generation and diverts these cells to the Th9 effector cell lineage, in part by inducing chromatin remodeling at the Foxp3 and Il9 loci via regulation of histone acetylation (24). Induction of STAT6 after GITR ligation of iTregs also suggests that a similar GITR-dependent pathway in nTregs may enhance STAT6 competition with STAT5 for binding to CNS2, leading to diminished FoxP3 expression (12).…”

Phenotypical characterization of regulatory T cells in humans and rodents

“…The role of GITR on T regs is controversial in the periphery, as GITR engagement favours the expansion of competent functional T regs preferentially [88]; however, other reports have suggested that signalling mediated by GITR in T regs leads to down-regulation of different pathways that control their suppressive function [89]. Moreover, it was proposed recently that GITR can inhibit FoxP3 cell induction, and in turn induce polarization to Th9 1 cells mediated by epigenetic changes [90]. Fig.…”