Single-cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4+ T cell perturbations

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dc.contributor.authorZemmour, David
dc.contributor.authorCharbonnier, Louis-Marie
dc.contributor.authorLeon, Juliette
dc.contributor.authorSix, Emmanuelle
dc.contributor.authorKeles, Sevgi
dc.contributor.authorDelville, Marianne
dc.contributor.authorBenamar, Mehdi
dc.date.accessioned2024-02-23T14:16:44Z
dc.date.available2024-02-23T14:16:44Z
dc.date.issued2021
dc.departmentNEÜen_US
dc.description.abstractFOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (T-reg) cells. CD4(+) T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous T-reg-like cells, some very similar to normal T-reg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4(+) T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal T-reg cells exerted dominant suppression, quenching the disease signature and revealing in mutant T-reg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes T-reg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering T-reg cell dysfunction. Accordingly, interleukin-2 treatment improved the T-reg-like compartment and survival. FOXP3 deficiency leads to dramatic loss of immune homeostasis. This multicenter collaborative group finds that loss of FOXP3 function only disrupts a few core genes, but this unmasks a degree of systemic inflammation, and it is this environment that then strongly perturbs T-reg cells.en_US
dc.description.sponsorshipNational Institutes of Health [AI116834, AI150686, AI085090, AI153174]; Institut National de la Sante et Recherche Medicale; European Union Seventh Framework [269037, 261387]; Horizon 2020 [693762]; Agence Nationale pour la Recherche (Investissement d'Avenir) [ANR-10-IAHU-01]; INSERM Poste d'Accueil; Arthur Sachs scholarship; European Research Council (ERC) [269037] Funding Source: European Research Council (ERC)en_US
dc.description.sponsorshipWe thank M. Levings and A. Rudensky for insightful discussions and K. Hattori, C. Araneo, K. Seddu and the Klarman Cell Observatory team for help with mice, cell sorting and single-cell profiling. This work was funded by grants from the National Institutes of Health to C. Benoist and D.M. (AI116834 and AI150686), T.A.C. (AI085090) and L.M.C. (AI153174); the Institut National de la Sante et Recherche Medicale; the European Union Seventh Framework (269037 and 261387) and Horizon 2020 (693762); and the Agence Nationale pour la Recherche (Investissement d'Avenir ANR-10-IAHU-01) to I.A., E.S., M.D., J.L., M.C., B.N., F.R.L., F.R. and N.C.B. J.L. was supported by an INSERM Poste d'Accueil and an Arthur Sachs scholarship.en_US
dc.identifier.doi10.1038/s41590-021-00910-8
dc.identifier.endpage+en_US
dc.identifier.issn1529-2908
dc.identifier.issn1529-2916
dc.identifier.issue5en_US
dc.identifier.pmid33833438en_US
dc.identifier.scopus2-s2.0-85104072956en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage607en_US
dc.identifier.urihttps://doi.org/10.1038/s41590-021-00910-8
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12764
dc.identifier.volume22en_US
dc.identifier.wosWOS:000638036600001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherNature Portfolioen_US
dc.relation.ispartofNature Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleSingle-cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4+ T cell perturbationsen_US
dc.typeArticleen_US

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