FOXP3 exon 2 controls Treg stability and autoimmunity

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 a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 Delta E2). The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear. In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome. Mice with Foxp3 exon 2 deletion have excessive follicular helper T (T-FH) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 Delta E2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, the FOXP3 Delta E2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without altered binding to these gene loci. These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains T-reg stability and immune homeostasis.

Automated summary

In this study, researchers discovered that the human FOXP3 gene encodes two major isoforms through alternative splicing. Patients who only express the shorter isoform may develop immunodeficiency and autoimmune diseases. Mice with the deletion of Foxp3 exon 2 also develop autoimmune diseases. The FOXP3 Delta E2 isoform allows increased expression of certain cytokines while decreasing the expression of positive regulators of Foxp3, leading to an unstable regulatory T cell phenotype.