T cell receptor signaling induces expression of lysine demethylase KDM6B to maintainTreg homeostasis.

Regulatory T (Treg) cells expressing Forkhead Box P3 (FOXP3) play crucial roles in maintaining immune tolerance and tissue integrity. EZH2, a Histone H3 lysine 27 (H3K27) methyltransferase, is known as a key regulator of Treg cell identity and suppressive function upon activation. Here, we demonstrate that the H3K27 lysine demethylase KDM6B, which catalyzes the opposing reaction to EZH2, was also required for Treg cell identity and function after activation. Treg-specific deletion of Kdm6b impaired tissue Treg cell fate and function. KDM6B was upregulated following T cell antigen receptor (TCR) signaling in Treg cells and contributed to the regulation of Treg-associated gene expression through both direct and indirect mechanisms. A subset of Treg functional genes were direct targets of KDM6B and were co-occupied by FOXP3 at cis-regulatory regions, where KDM6B recruitment limited H3K27me3 accumulation. More broadly, KDM6B-dependent H3K27 demethylation facilitated Treg gene expression programs that supported tissue Treg homeostasis.