Gu and Zhao et al. showed that exon 2 deletion from Foxp3 freed the C-terminal FKH binding domain from N-terminal masking and enhanced target DNA binding. Mice expressing Foxp3Δ2 in Tregs had immune profiles similar to WT littermates, but a higher proportion of dysfunctional Tregs and greater antitumor activity in a melanoma model. Peripheral Foxp3Δ2-expressing thymus-derived (t)Tregs had greater Foxp3Δ2/Batf promoter binding, lower expression of effector proteins and BATF, and lower responses to TCR and IL-2 agonism. Interruption of the FoxP3/RORγt axis by Foxp3Δ2 in colonic peripherally induced (p)Tregs enhanced adaptation to the gut environment.
Contributed by Paula Hochman
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.
Author Info: (1) CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China; Department of Savaid Medical S
Author Info: (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; Department of Savaid Medical School, University of Chinese Academy of Sciences (CAS), Beijing 100049, China. (3) CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (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. (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 Chinese Academy of Sciences (CAS), Beijing 100049, China. (6) 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. (7) 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. (8) CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China. (9) CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China. (10) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, China. (11) 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. (12) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, China. (13) 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.
