The histone lysine methyltransferase MLL1 regulates the activation and functional specialization of regulatory T cells

Ting Wang; Jie Guo; Liping Li; Qiuzhu Jin; Fuping Zhang; Baidong Hou; Yan Zhang; Xuyu Zhou

doi:10.1016/j.celrep.2024.114222

The histone lysine methyltransferase MLL1 regulates the activation and functional specialization of regulatory T cells

Cell Rep. 2024 May 10;43(5):114222. doi: 10.1016/j.celrep.2024.114222. Online ahead of print.

Authors

Ting Wang¹, Jie Guo², Liping Li¹, Qiuzhu Jin¹, Fuping Zhang¹, Baidong Hou³, Yan Zhang⁴, Xuyu Zhou⁵

Affiliations

¹ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China; Department of Savaid Medical School, University of the Chinese Academy of Sciences, Beijing 100049, China.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China.
³ Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, China.
⁴ Department of Hematology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: yan.zhang19510@shgh.cn.
⁵ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China; Department of Savaid Medical School, University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhouxy@im.ac.cn.

PMID: 38735046
DOI: 10.1016/j.celrep.2024.114222

Abstract

The activation and specialization of regulatory T cells (Tregs) are crucial for maintaining immune self-tolerance; however, the regulation of these processes by histone modifications is not fully understood. Here, we show that T cell-specific deletion of the lysine methyltransferase MLL1 results in a spontaneous lymphocyte proliferation phenotype in aged mice without disturbing the development of conventional T cells and Tregs. Treg-specific MLL1 ablation leads to a systemic autoimmune disease associated with Treg dysfunction. Moreover, RNA sequencing demonstrates that the induction of multiple genes involved in Treg activation, functional specialization, and tissue immigration is defective in MLL1-deficient Tregs. This dysregulation is associated with defects in H3K4 trimethylation at these genes' transcription start sites. Finally, using a T-bet fate-mapping mouse system, we determine that MLL1 is required to establish stable Th1-type Tregs. Thus, MLL1 is essential in optimal Treg function by providing a coordinated chromatin context for activation and specialization.

Keywords: CP: Immunology; H3K4 trimethylation; MLL1; T-bet; Treg; autoimmunity.