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The splicing isoform Foxp3∆2 differentially regulates tTregs and pTregs homeostasis

ABSTRACT: Foxp3 is the master transcription factor for the 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 Foxp3∆2-bearing tTregs in the peripheral lymphoid organ are less sensitive to TCR due to the enhanced binding of Foxp3∆2 to the Batf promoter and are unsusceptible to IL-2. In contrast, among RORγt+ pTregs in the large intestine, Foxp3∆2 pTregs express much more RORγt-related genes conferring a competitive advantage. Together, our results reveal that alternative splicing of exon 2 generates a constitutively active form of Foxp3, which plays a differential role in regulating tTregs and pTregs homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE236356 | GEO | 2023/11/19

REPOSITORIES: GEO

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