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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:p>\n                    Methyl-CpG-binding domain protein 3 (MBD3), an essential component of the nucleosome remodeling and deacetylase (NuRD) complex, controls chromatin accessibility at lineage-specific transcriptional enhancers and promoters during hematopoietic cell differentiation. Here, we have shown that MBD3 deficiency in the T cell compartment resulted in spontaneous development of T cell\u2013mediated multiorgan autoimmune diseases including fatal autoimmune myocarditis. The MBD3-deficient mice notably showed a significant reduction of CD25\n                    <jats:sup>+<\/jats:sup>\n                    Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    regulatory T (Treg) cells in both the thymus and periphery without much affecting the development and function of conventional T (Tconv) cells. Mixed bone marrow (BM) chimeras reconstituted with wild-type and MBD3-deficient BM revealed a cell-intrinsic defect in thymic Treg cell lineage differentiation in MBD3-deficient cells. Transcriptional, phenotypic, and functional analyses of thymocyte subsets further revealed that MBD3 deficiency particularly affected the activation of a Treg-specific enhancer of the\n                    <jats:italic toggle=\"yes\">Il2ra<\/jats:italic>\n                    gene encoding CD25, hence impaired CD25 expression in immature CD4 single-positive thymocytes (ImCD4SP) but not in peripheral T cells. The impairment markedly limited thymic Treg precursor cell generation and substantially reduced overall thymic Treg cell output. By contrast, MBD3 deficiency scarcely impacted the TGF-\u03b2\/IL-2-dependent in vitro Treg cell generation from Tconv cells. Thus, Treg-specific developmental properties such as high IL-2\/CD25 dependency of their thymic differentiation may render them more sensitive than Tconv cells to epigenetic changes of the whole T cell compartment. The results provide a mechanistic basis by which general epigenomic alterations in the T cell compartment can be causative of autoimmune and other immunological diseases through selectively affecting thymic Treg cell development.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2626262123","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:36:36Z","timestamp":1791999396000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Autoimmunity induced by epigenome alteration affecting thymic Treg cell development"],"prefix":"10.1073","volume":"123","author":[{"given":"Jia","family":"Long","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Experimental Immunology, Immunology Frontier Research Center, University of Osaka","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Experimental Immunology, Immunology Frontier Research Center, University of Osaka","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Arai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Experimental Immunology, Immunology Frontier Research Center, University of Osaka","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamami","family":"Nakamura","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Experimental Immunology, Immunology Frontier Research Center, 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