Setd2 determines distinct properties of intestinal ILC3 subsets to regulate intestinal immunity.

Subsets of group 3 innate lymphoid cells (ILC3s) are heterogeneous in development and function and play differential roles in intestinal immunity. Histone modifications are involved in the fate commitment of immune cells, including ILC3s. Here, we report that deletion of Setd2, histone H3K36 methyltransferase, in ILC3s results in increased generation of NKp46ILC3s with enhanced cytotoxic signatures and tumor-suppressive capacity. Meanwhile, Rag1RorcSetd2 mice have fewer CCR6ILC3s and less defective solitary intestinal lymphoid tissue formation, accompanied by reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) production by NKp46ILC3s and decreased CD11bCD103 dendritic cell accumulation. The deficiency of Setd2NKp46ILC3s may contribute to disturbed RORγtTreg homeostasis and intestinal inflammation in Rag1RorcSetd2 mice upon T cell reconstitution. Setd2 regulates genome accessibility imprinting gene mRNA expression, with a more profound effect on NKp46ILC3s than NKp46ILC3s. Therefore, Setd2 determines distinct chromatin status and transcriptomic programs of ILC3 subsets to affect their function and intestinal immunity.