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
Affiliations
Ting Wang
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
Jie Guo
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China
Liping Li
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
Qiuzhu Jin
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
Fuping Zhang
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
Baidong Hou
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, China
Yan Zhang
Department of Hematology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Corresponding author
Xuyu Zhou
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; Corresponding author
Summary: 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.
