Du, JianguangWang, QunYang, ShuangshuangChen, SiFu, YongyaoSpath, SabineDomeier, PhillipHagin, DavidAnover-Sombke, StephanieHaouili, MayaLiu, ShengWan, JunHan, LeiLiu, JuliYang, LeiSangani, NeelLi, YujingLu, XiongbinJanga, Sarath ChandraKaplan, Mark H.Torgerson, Troy R.Ziegler, Steven F.Zhou, Baohua2023-10-032023-10-032022Du J, Wang Q, Yang S, et al. FOXP3 exon 2 controls Treg stability and autoimmunity. Sci Immunol. 2022;7(72):eabo5407. doi:10.1126/sciimmunol.abo5407https://hdl.handle.net/1805/36119Differing 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 ΔE2). 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 (TFH) 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 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, the FOXP3 ΔE2 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 Treg stability and immune homeostasis.en-USPublisher PolicyAutoimmunityExonsForkhead transcription factorsProtein isoformsRegulatory T-LymphocytesArticle