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The self-tolerance of T cells is established by negative selection of autoreactive T cells that bind to TRAs. To increase the diversity of TRAs, a fraction of mTECs terminally differentiates into distinct subsets resembling atypical types of epithelial cells in specific peripheral tissues. As such, thymic tuft cells that express peripheral tuft cell genes have recently emerged. Here, we show that the transcription factor SRY-box transcription factor 4 (Sox4) is highly expressed in mTECs and is essential for the development of thymic tuft cells. Mice lacking Sox4 specifically in TECs had a significantly reduced number of thymic tuft cells with no effect on the differentiation of other mTEC subsets, including autoimmune regulator (Aire)+ and Ccl21a+ mTECs. Furthermore, Sox4 expression was diminished in mice deficient in TEC-specific lymphotoxin \u03b2 receptor (LT\u03b2R), indicating a role for the LT\u03b2R-Sox4 axis in the differentiation of thymic tuft cells. Given that Sox4 promotes differentiation of peripheral tuft cells, our findings suggest that mTECs employ the same transcriptional program as peripheral epithelial cells. This mechanism may explain how mTECs diversify peripheral antigen expression to project an immunological self within the thymic medulla.<\/jats:p>","DOI":"10.1093\/intimm\/dxab098","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T12:02:39Z","timestamp":1634904159000},"page":"45-52","source":"Crossref","is-referenced-by-count":15,"title":["The transcription factor Sox4 is required for thymic tuft cell development"],"prefix":"10.1093","volume":"34","author":[{"given":"Nanami","family":"Mino","sequence":"first","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]},{"name":"Department of Allergy and Rheumatology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryunosuke","family":"Muro","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayami","family":"Ota","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Nitta","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Lefebvre","sequence":"additional","affiliation":[{"name":"Leonard and Madlyn Abramson Pediatric Research Center, Children\u2019s Hospital of Philadelphia , Philadelphia, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2384-3062","authenticated-orcid":false,"given":"Takeshi","family":"Nitta","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keishi","family":"Fujio","sequence":"additional","affiliation":[{"name":"Department of Allergy and Rheumatology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Takayanagi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,23]]},"reference":[{"key":"2024102211025291500_CIT0001","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1146\/annurev-immunol-051116-052320","article-title":"Thymic epithelial cells","volume":"35","author":"Abramson","year":"2017","journal-title":"Annu. 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Immunol."},{"key":"2024102211025291500_CIT0005","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/imr.12985","article-title":"The fibroblast: an emerging key player in thymic T cell selection","volume":"302","author":"Nitta","year":"2021","journal-title":"Immunol. Rev."},{"key":"2024102211025291500_CIT0006","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/ni.3675","article-title":"The transcriptional regulator Aire binds to and activates super-enhancers","volume":"18","author":"Bansal","year":"2017","journal-title":"Nat. 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Cell Biol."},{"key":"2024102211025291500_CIT0019","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.1084\/jem.20172021","article-title":"SOX4 controls invariant NKT cell differentiation by tuning TCR signaling","volume":"215","author":"Malhotra","year":"2018","journal-title":"J. Exp. Med."},{"key":"2024102211025291500_CIT0020","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/ni.2362","article-title":"The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-\u03b2 and suppresses T(H)2 differentiation","volume":"13","author":"Kuwahara","year":"2012","journal-title":"Nat. Immunol."},{"key":"2024102211025291500_CIT0021","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.immuni.2013.01.010","article-title":"A network of high-mobility group box transcription factors programs innate interleukin-17 production","volume":"38","author":"Malhotra","year":"2013","journal-title":"Immunity"},{"key":"2024102211025291500_CIT0022","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/1471-213X-7-69","article-title":"Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus","volume":"7","author":"Gordon","year":"2007","journal-title":"BMC Dev. Biol."},{"key":"2024102211025291500_CIT0023","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1002\/dvg.20358","article-title":"Generation of mice harboring a Sox4 conditional null allele","volume":"45","author":"Penzo-M\u00e9ndez","year":"2007","journal-title":"Genesis"},{"key":"2024102211025291500_CIT0024","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/ni.2731","article-title":"Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells","volume":"14","author":"Lee","year":"2013","journal-title":"Nat. Immunol."},{"key":"2024102211025291500_CIT0025","doi-asserted-by":"crossref","first-page":"575764","DOI":"10.3389\/fimmu.2020.575764","article-title":"Impact of aging on the phenotype of invariant natural killer T cells in mouse thymus","volume":"11","author":"Papadogianni","year":"2020","journal-title":"Front. 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Commun."},{"key":"2024102211025291500_CIT0028","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.immuni.2010.02.011","article-title":"Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection","volume":"32","author":"Wang","year":"2010","journal-title":"Immunity"},{"key":"2024102211025291500_CIT0029","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1084\/jem.20030794","article-title":"Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR","volume":"198","author":"Boehm","year":"2003","journal-title":"J. Exp. Med."},{"key":"2024102211025291500_CIT0030","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.coi.2010.12.002","article-title":"Cytokine crosstalk for thymic medulla formation","volume":"23","author":"Nitta","year":"2011","journal-title":"Curr. Opin. 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