Wdr82-COMPASS coordinates Foxp3 and TCR signaling to sustain T reg cell control of microbiota-driven intestinal inflammation

Regulatory T cells (T reg cells) maintain immune tolerance, but how broadly acting epigenetic pathways are selectively used by T reg cells versus conventional T cells (T conv cells) remains unclear. Here, we identify the COMPASS–trimethylation of histone H3 lysine 4 (H3K4me3) pathway, through its Wdr82 component, as a key epigenetic regulator that preferentially supports T reg cell development and function. Although Wdr82 deficiency broadly impairs T cell activation, T cell–specific deletion paradoxically causes progressive, microbiota-dependent intestinal inflammation and expansion of inflammatory T conv cell programs. This pathology is prevented by microbiome depletion or transfer of wild-type T reg cells, indicating a primary defect in T reg cell–mediated tolerance. Mechanistically, Wdr82/COMPASS promotes Foxp3 induction, maintains H3K4me3 and chromatin accessibility at T reg cell–associated genes, and restrains effector programs within the T reg cell lineage. Foxp3 coordinates with COMPASS components in a T cell receptor/costimulation-dependent manner, linking antigen receptor signaling to chromatin regulation. Together, these findings reveal selective integration of a broadly active epigenetic pathway into the Foxp3-centered regulatory hierarchy that sustains T reg cell control of microbiota-driven intestinal inflammation.