FOXP3 exon 2 controls Treg stability and autoimmunity
dc.contributor.author | Du, Jianguang | |
dc.contributor.author | Wang, Qun | |
dc.contributor.author | Yang, Shuangshuang | |
dc.contributor.author | Chen, Si | |
dc.contributor.author | Fu, Yongyao | |
dc.contributor.author | Spath, Sabine | |
dc.contributor.author | Domeier, Phillip | |
dc.contributor.author | Hagin, David | |
dc.contributor.author | Anover-Sombke, Stephanie | |
dc.contributor.author | Haouili, Maya | |
dc.contributor.author | Liu, Sheng | |
dc.contributor.author | Wan, Jun | |
dc.contributor.author | Han, Lei | |
dc.contributor.author | Liu, Juli | |
dc.contributor.author | Yang, Lei | |
dc.contributor.author | Sangani, Neel | |
dc.contributor.author | Li, Yujing | |
dc.contributor.author | Lu, Xiongbin | |
dc.contributor.author | Janga, Sarath Chandra | |
dc.contributor.author | Kaplan, Mark H. | |
dc.contributor.author | Torgerson, Troy R. | |
dc.contributor.author | Ziegler, Steven F. | |
dc.contributor.author | Zhou, Baohua | |
dc.contributor.department | Pediatrics, School of Medicine | |
dc.date.accessioned | 2023-10-03T15:44:49Z | |
dc.date.available | 2023-10-03T15:44:49Z | |
dc.date.issued | 2022 | |
dc.description.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 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. | |
dc.eprint.version | Author's manuscript | |
dc.identifier.citation | Du 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.abo5407 | |
dc.identifier.uri | https://hdl.handle.net/1805/36119 | |
dc.language.iso | en_US | |
dc.publisher | American Association for the Advancement of Science | |
dc.relation.isversionof | 10.1126/sciimmunol.abo5407 | |
dc.relation.journal | Science Immunology | |
dc.rights | Publisher Policy | |
dc.source | PMC | |
dc.subject | Autoimmunity | |
dc.subject | Exons | |
dc.subject | Forkhead transcription factors | |
dc.subject | Protein isoforms | |
dc.subject | Regulatory T-Lymphocytes | |
dc.title | FOXP3 exon 2 controls Treg stability and autoimmunity | |
dc.type | Article |