The splicing isoform Foxp3Δ2 differentially regulates tTreg and pTreg homeostasis
Qianchong Gu,
Xiufeng Zhao,
Jie Guo,
Qiuzhu Jin,
Ting Wang,
Wei Xu,
Liping Li,
Jianhua Zhang,
Wei Zhang,
Sheng Hong,
Fuping Zhang,
Baidong Hou,
Xuyu Zhou
Affiliations
Qianchong Gu
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 Chinese Academy of Sciences (CAS), Beijing 100049, China
Xiufeng Zhao
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 Chinese Academy of Sciences (CAS), Beijing 100049, China
Jie Guo
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, 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 Chinese Academy of Sciences (CAS), Beijing 100049, China
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 Chinese Academy of Sciences (CAS), Beijing 100049, China
Wei Xu
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 Chinese Academy of Sciences (CAS), Beijing 100049, 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 Chinese Academy of Sciences (CAS), Beijing 100049, China
Jianhua Zhang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China
Wei Zhang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China
Sheng Hong
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, 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 Chinese Academy of Sciences (CAS), Beijing 100049, China
Baidong Hou
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, China
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 Chinese Academy of Sciences (CAS), Beijing 100049, China; Corresponding author
Summary: Foxp3 is the master transcription factor for regulatory T cells (Tregs). Alternative splicing of human Foxp3 results in the expression of two isoforms: the full length and an exon 2-deleted protein. Here, AlphaFold2 predictions and in vitro experiments demonstrate that the N-terminal domain of Foxp3 inhibits DNA binding by moving toward the C terminus and that this movement is mediated by exon 2. Consequently, we find that Foxp3Δ2-bearing thymus-derived Tregs (tTregs) in the peripheral lymphoid organ are less sensitive to T cell receptor (TCR) stimulation due to the enhanced binding of Foxp3Δ2 to the Batf promoter and are hyporesponsive to interleukin-2 (IL-2). In contrast, among RORγt+ peripherally induced Tregs (pTregs) in the large intestine, Foxp3Δ2 pTregs express many more RORγt-related genes, conferring a competitive advantage. Together, our results reveal that alternative splicing of exon 2 generates an active form of Foxp3, which plays a differential role in regulating tTreg and pTreg homeostasis.
