KMT2D maintains Treg homeostasis and protects against inflammatory diseases by regulating the purinergic channel P2X7 level

Regulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance through the prevention of inflammatory and autoimmune responses. The histone methyltransferase KMT2D is indispensable for induced Treg (iTreg) cell differentiation, its role in the differentiation and function of Treg cells in vivo has remained largely unknown. Here, we demonstrate that KMT2D is critical for the differentiation and function of effector activated Treg (aTreg) cells. We found that KMT2D deficiency in Treg cells impairs aTreg generation and exacerbates inflammatory conditions, such as allergic airway inflammation and colitis. Mechanistically, KMT2D regulates aTreg differentiation through TCR signaling. Furthermore, KMT2D modulates Ca2+ influx by promoting the expression of purinergic receptor P2X7 through H3K4me3 deposition. Collectively, our fundings highlight a pivotal role for KMT2D in Treg cell homeostasis and function, potentially offering a new therapeutic strategy for treating inflammatory diseases. Overall design: Spleen CD4+FoxP3+ Treg cells from Foxp3YFP-CreKmt2d+/+ and Foxp3YFP-CreKmt2dfl/fl mice were sorted. The sorted Treg cells from three Foxp3YFP-CreKmt2d+/+ mice were pooled into one sample, while Treg cells from three Foxp3YFP-CreKmt2dfl/fl mice were combined into a separate sample for scRNA-seq.