A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells

• Published in: Immunity (Cambridge, Mass.) Mass.), 2019-02, Vol.50 (2), p.362-377.e6
• Main Authors: Van Gool, Frédéric, Nguyen, Michelle L.T., Mumbach, Maxwell R., Satpathy, Ansuman T., Rosenthal, Wendy L., Giacometti, Simone, Le, Duy T., Liu, Weihong, Brusko, Todd M., Anderson, Mark S., Rudensky, Alexander Y., Marson, Alexander, Chang, Howard Y., Bluestone, Jeffrey A.
• Format: Article
• Language: English
• Subjects: Advisors; Animals; autoimmunity; Cell Differentiation - genetics; Cell Differentiation - immunology; Child; Chromatin; Cytokines; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Deoxyribonucleic acid; DNA; DNA sequencing; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Foxp3; Foxp3 protein; GATA3; Gene Expression Regulation; Gene silencing; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - immunology; Genetic Diseases, X-Linked - metabolism; Genomic analysis; Genomics; Genotype & phenotype; Helper cells; Homeostasis; Humans; Immune response; Immune system; Immunological tolerance; Immunoprecipitation; Immunoregulation; IPEX; Laboratories; Lymphocytes; Lymphocytes T; Male; Mice, Inbred C57BL; Mice, Knockout; Mutation; Patients; Polyendocrinopathies, Autoimmune - genetics; Polyendocrinopathies, Autoimmune - immunology; Polyendocrinopathies, Autoimmune - metabolism; Proteins; regulatory T cells; Ribonucleic acid; RNA; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th2 Cells - immunology; Th2 Cells - metabolism; Th2-like Treg; Transcription factors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.12.016

Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells. [Display omitted] •IPEX mutation M370I leads to unrestrained Th2 immune response•M370I mutation generates Th2-like Treg cells expressing GATA3 and Th2 cytokines•M370I mutation induces de novo Foxp3 binding sites in the Th2 locus•M370I Treg cells have increased chromatin interaction at the Th2 locus Naturally occurring FOXP3 mutations provide unique opportunities to leverage clinical observations to increase our understanding of fundamental Treg cell biology. Van Gool et al. identify a mutation in the domain-swap interface of FOXP3 in IPEX patients and demonstrate a direct role for the mutant FOXP3 in reprogramming Treg cells to acquire a Th2-like phenotype, leading to Th2-mediated autoimmunity.