GITR subverts Foxp3(+) Tregs to boost Th9 immunity through regulation of histone acetylation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26365427.
- Also identified by DOI 10.1038/ncomms9266 and PMC identifier 4570275.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Glucocorticoid-Induced TNFR-Related Protein
- Histones
- Melanoma, Experimental
- T-Lymphocyte Subsets
- T-Lymphocytes, Helper-Inducer
- T-Lymphocytes, Regulatory
- p300-CBP Transcription Factors