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Here, we identify that miR-155, a microRNA whose expression in T reg cells has previously been shown to be crucial for their development and homeostasis, also contributes to thymic T reg (tT reg) cell differentiation by promoting mTEC maturation. Mechanistically, we show that RANKL stimulation induces expression of miR-155 to safeguard the thymic medulla through targeting multiple known and previously uncharacterized molecules within the TGF\u03b2 signaling pathway, which is recognized for its role in restricting the maturation and expansion of mTECs. Our work uncovers a miR-155\u2013TGF\u03b2 axis in the thymic medulla to determine mTEC maturity and, consequently, the quantity of tT reg cells and suggests that miR-155 ensures proper tT reg cell development in both cell-intrinsic and -extrinsic manners.<\/jats:p>","DOI":"10.1084\/jem.20192423","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T13:29:00Z","timestamp":1604064540000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["miR-155 promotes T reg cell development by safeguarding medullary thymic epithelial cell maturation"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0214-4847","authenticated-orcid":true,"given":"Jiayi","family":"Dong","sequence":"first","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, CA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4258-7271","authenticated-orcid":true,"given":"Lindsey M.","family":"Warner","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, CA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6547-4739","authenticated-orcid":true,"given":"Ling-Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, CA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9984-3459","authenticated-orcid":true,"given":"Mei-Chi","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, CA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0860-1401","authenticated-orcid":true,"given":"Ryan M.","family":"O'Connell","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute and the Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9727-0036","authenticated-orcid":true,"given":"Li-Fan","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, CA 1"},{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA 3"},{"name":"Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 4"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2020,10,30]]},"reference":[{"key":"2023072801395633800_bib1","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.immuni.2008.06.015","article-title":"The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance","volume":"29","author":"Akiyama","year":"2008","journal-title":"Immunity."},{"key":"2023072801395633800_bib2","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1126\/science.1075958","article-title":"Projection of an immunological self shadow within the thymus by the aire protein","volume":"298","author":"Anderson","year":"2002","journal-title":"Science."},{"key":"2023072801395633800_bib3","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/ni1444","article-title":"Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells","volume":"8","author":"Aschenbrenner","year":"2007","journal-title":"Nat. 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