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

doi:10.1016/j.celrep.2023.112877

The splicing isoform Foxp3Δ2 differentially regulates tTreg and pTreg homeostasis

Cell Rep. 2023 Aug 29;42(8):112877. doi: 10.1016/j.celrep.2023.112877. Epub 2023 Jul 26.

Authors

Qianchong Gu¹, Xiufeng Zhao¹, Jie Guo², Qiuzhu Jin¹, Ting Wang¹, Wei Xu¹, Liping Li¹, Jianhua Zhang², Wei Zhang², Sheng Hong³, Fuping Zhang¹, Baidong Hou³, Xuyu Zhou⁴

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 Chinese Academy of Sciences (CAS), 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 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. Electronic address: zhouxy@im.ac.cn.

PMID: 37498744
DOI: 10.1016/j.celrep.2023.112877

Abstract

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.

Keywords: CP: Immunology; Foxp3; Treg; alternative splicing; conformation regulation.