A mutation in the transcription factor Foxp3 drives T helper 2 effector function in regulatory T cells Journal Article
| Authors: | Van Gool, F.; Nguyen, M. L. T.; Mumbach, M. R.; Satpathy, A. T.; Rosenthal, W. L.; Giacometti, S.; Le, D. T.; Liu, W.; Brusko, T. M.; Anderson, M. S.; Rudensky, A. Y.; Marson, A.; Chang, H. Y.; Bluestone, J. A. |
| Article Title: | A mutation in the transcription factor Foxp3 drives T helper 2 effector function in regulatory T cells |
| Abstract: | 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. 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. © 2018 Elsevier Inc. |
| Keywords: | clinical article; controlled study; protein expression; gene mutation; human cell; case report; nonhuman; flow cytometry; transcription factor foxp3; animal cell; mouse; phenotype; animal tissue; transcription factor gata 3; thrombocytopenia; gene locus; in vivo study; cell differentiation; high throughput screening; enzyme linked immunosorbent assay; regulatory t lymphocyte; th2 cell; infant; guanine; chromatin; gene interaction; cytokine production; autoimmunity; amino acid; dna sequence; isoleucine; pathogenicity; insulin dependent diabetes mellitus; cell interaction; thymocyte; methionine; lymphocyte function; chromatin assembly and disassembly; nuclear reprogramming; regulatory t cells; nucleotide; adenine; immunoglobulin e; foxp3; gata3; eosinophil count; ipex; eczema; human; male; priority journal; article; crispr associated protein; gene editing; th2-like treg; ipex syndrome |
| Journal Title: | Immunity |
| Volume: | 50 |
| Issue: | 2 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2019-02-19 |
| Start Page: | 362 |
| End Page: | 377.e6 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2018.12.016 |
| PUBMED: | 30709738 |
| PROVIDER: | scopus |
| PMCID: | PMC6476426 |
| DOI/URL: | |
| Notes: | Source: Scopus |
