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

doi:10.1016/j.celrep.2022.110530

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

Cell Rep. 2022 Mar 15;38(11):110530. doi: 10.1016/j.celrep.2022.110530.

Authors

Jiali Chang¹, Xiaojuan Ji¹, Tian Deng², Jinxin Qiu¹, Zhaoyun Ding¹, Zhao Li¹, Yanhui Ma³, Xiaoyu Hu⁴, Li Li⁵, Ju Qiu⁶

Affiliations

¹ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
² Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.
³ Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
⁴ Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing 100084, China.
⁵ State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: lil@sjtu.edu.cn.
⁶ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: qiuju@sibs.ac.cn.

PMID: 35294891
DOI: 10.1016/j.celrep.2022.110530

Abstract

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^-/-Rorc^CreSetd2^flox/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^-/-Rorc^CreSetd2^flox/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.

Keywords: CP: Immunology; Setd2; group 3 innate lymphoid cells; intestinal immunity; regulatory T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Histone Methyltransferases
Histone-Lysine N-Methyltransferase / genetics
Homeodomain Proteins / genetics
Immunity, Innate*
Intestinal Mucosa
Intestines
Lymphocytes*
Mice

Substances

Homeodomain Proteins
Histone Methyltransferases
Histone-Lysine N-Methyltransferase
SETD2 protein, mouse