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

Jiali Chang, Xiaojuan Ji, Tian Deng, Jinxin Qiu, Zhaoyun Ding, Zhao Li, Yanhui Ma, Xiaoyu Hu, Li Li, Ju Qiu

Cell reports 2022 Mar 15

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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 NKp46+ILC3s with enhanced cytotoxic signatures and tumor-suppressive capacity. Meanwhile, Rag1-/-RorcCreSetd2flox/flox mice have fewer CCR6+ILC3s and less defective solitary intestinal lymphoid tissue formation, accompanied by reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) production by NKp46-ILC3s and decreased CD11b+CD103+ dendritic cell accumulation. The deficiency of Setd2-/-NKp46-ILC3s may contribute to disturbed RORγt+Treg homeostasis and intestinal inflammation in Rag1-/-RorcCreSetd2flox/flox mice upon T cell reconstitution. Setd2 regulates genome accessibility imprinting gene mRNA expression, with a more profound effect on NKp46+ILC3s than NKp46-ILC3s. Therefore, Setd2 determines distinct chromatin status and transcriptomic programs of ILC3 subsets to affect their function and intestinal immunity. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Jiali Chang, Xiaojuan Ji, Tian Deng, Jinxin Qiu, Zhaoyun Ding, Zhao Li, Yanhui Ma, Xiaoyu Hu, Li Li, Ju Qiu. Setd2 determines distinct properties of intestinal ILC3 subsets to regulate intestinal immunity. Cell reports. 2022 Mar 15;38(11):110530