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Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction

Mutations of the transcription factor FoxP3 in patients with “IPEX” (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, withou...

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Autores principales: Leon, Juliette, Chowdhary, Kaitavjeet, Zhang, Wenxiang, Ramirez, Ricardo N., André, Isabelle, Hur, Sun, Mathis, Diane, Benoist, Christophe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10565790/
https://www.ncbi.nlm.nih.gov/pubmed/37605532
http://dx.doi.org/10.1016/j.celrep.2023.113018
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author Leon, Juliette
Chowdhary, Kaitavjeet
Zhang, Wenxiang
Ramirez, Ricardo N.
André, Isabelle
Hur, Sun
Mathis, Diane
Benoist, Christophe
author_facet Leon, Juliette
Chowdhary, Kaitavjeet
Zhang, Wenxiang
Ramirez, Ricardo N.
André, Isabelle
Hur, Sun
Mathis, Diane
Benoist, Christophe
author_sort Leon, Juliette
collection PubMed
description Mutations of the transcription factor FoxP3 in patients with “IPEX” (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, without genetic and environmental confounders, six human FOXP3 missense mutations are engineered into mice. Two classes of mutations emerge from combined immunologic and genomic analyses. A mutation in the DNA-binding domain shows the same lymphoproliferation and multiorgan infiltration as complete FoxP3 knockouts but delayed by months. Tregs expressing this mutant FoxP3 are destabilized by normal Tregs in heterozygous females compared with hemizygous males. Mutations in other domains affect chromatin opening differently, involving different cofactors and provoking more specific autoimmune pathology (dermatitis, colitis, diabetes), unmasked by immunological challenges or incrossing NOD autoimmune-susceptibility alleles. This work establishes that IPEX disease heterogeneity results from the actual mutations, combined with genetic and environmental perturbations, explaining then the intra-familial variation in IPEX.
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spelling pubmed-105657902023-10-11 Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction Leon, Juliette Chowdhary, Kaitavjeet Zhang, Wenxiang Ramirez, Ricardo N. André, Isabelle Hur, Sun Mathis, Diane Benoist, Christophe Cell Rep Article Mutations of the transcription factor FoxP3 in patients with “IPEX” (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, without genetic and environmental confounders, six human FOXP3 missense mutations are engineered into mice. Two classes of mutations emerge from combined immunologic and genomic analyses. A mutation in the DNA-binding domain shows the same lymphoproliferation and multiorgan infiltration as complete FoxP3 knockouts but delayed by months. Tregs expressing this mutant FoxP3 are destabilized by normal Tregs in heterozygous females compared with hemizygous males. Mutations in other domains affect chromatin opening differently, involving different cofactors and provoking more specific autoimmune pathology (dermatitis, colitis, diabetes), unmasked by immunological challenges or incrossing NOD autoimmune-susceptibility alleles. This work establishes that IPEX disease heterogeneity results from the actual mutations, combined with genetic and environmental perturbations, explaining then the intra-familial variation in IPEX. 2023-08-29 2023-08-21 /pmc/articles/PMC10565790/ /pubmed/37605532 http://dx.doi.org/10.1016/j.celrep.2023.113018 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Leon, Juliette
Chowdhary, Kaitavjeet
Zhang, Wenxiang
Ramirez, Ricardo N.
André, Isabelle
Hur, Sun
Mathis, Diane
Benoist, Christophe
Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction
title Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction
title_full Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction
title_fullStr Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction
title_full_unstemmed Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction
title_short Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction
title_sort mutations from patients with ipex ported to mice reveal different patterns of foxp3 and treg dysfunction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10565790/
https://www.ncbi.nlm.nih.gov/pubmed/37605532
http://dx.doi.org/10.1016/j.celrep.2023.113018
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