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FOXP3 exon 2 controls Treg stability and autoimmunity [RNA-seq]

ABSTRACT: Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing – a longer isoform (FOXP3 FL) containing all the coding exons and the other shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans yet their differences in controlling regulatory T cell phenotype and functionality remains unclear. Here we show that patients expressing only the shorter isoform failed to maintain self-tolerance and developed IPEX syndrome. Mice with Foxp3 exon 2 deletion developed excessive TFH and GC B cell responses and systemic autoimmune disease with anti-dsDNA and anti-nuclear autoantibody production and immune-complex glomerulonephritis. Regulatory T cells expressing FOXP3 ΔE2 were unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, FOXP3 ΔE2 isoform allows increased expression of selected cytokines but decreased expression of a set of Foxp3 positive regulators without altered binding to these gene loci. We demonstrate that exon 2 of FOXP3 is required to maintain Treg stability and immune homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE199477 | GEO | 2022/06/27

REPOSITORIES: GEO

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