{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:25:21Z","timestamp":1789097121349,"version":"build-2803163510"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:00:00Z","timestamp":1692316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Murine IL-17-producing \u03b3\u03b4T (\u03b3\u03b4T17) cells are divided into two subsets: natural \u03b3\u03b4T17 (n\u03b3\u03b4T17) cells, whose development is restricted to the fetal thymus, and inducible \u03b3\u03b4T17 cells, which require antigen exposure for their IL-17 production and are presumed to develop from <jats:italic>Rorc<\/jats:italic><jats:sup>+<\/jats:sup><jats:italic>Il17a<\/jats:italic><jats:sup>-<\/jats:sup><jats:italic>CCR9<\/jats:italic><jats:sup>+<\/jats:sup> immature \u03b3\u03b4T17 cells in the adult thymus and whose T cell receptor (TCR) is biased toward V\u03b34. Although IL-23 is known to be involved in developing \u03b3\u03b4T17 cells, the roles of other cytokines, such as IL-21, which is involved in developing Th17 cells like IL-23, in the development, maintenance, and pathophysiology of \u03b3\u03b4T17 cells remain unknown. Here, we show that IL-21 is dispensable for the fetal thymic development of n\u03b3\u03b4T17 cells but is required for the peripheral maintenance of V\u03b34<jats:sup>+<\/jats:sup>n\u03b3\u03b4T17 cells. Upon stimulation with \u03b3\u03b4TCR, IL-1 plus IL-21 induces the proliferation of V\u03b34<jats:sup>+<\/jats:sup>n\u03b3\u03b4T17 cells via STAT3 as effectively as IL-1 plus IL-23. Using bone marrow chimeric mice, we demonstrated that immature \u03b3\u03b4T17 cells are produced <jats:italic>de novo<\/jats:italic> in the adult mice from donor adult bone marrow cells and that IL-21 is dispensable for their development. Instead, IL-21 is required to expand newly induced V\u03b34<jats:sup>+<\/jats:sup>\u03b3\u03b4T17 cells in the periphery upon immunization. Finally, using adoptive transfer experiments of \u03b3\u03b4T17 cells, we found that IL-21 receptors on \u03b3\u03b4T17 cells are involved in maintaining V\u03b34<jats:sup>+<\/jats:sup>\u03b3\u03b4T17 cells, subsequent infiltration of Th17 cells into the spinal cord, and exacerbation of experimental autoimmune encephalomyelitis. Collectively, IL-21 plays a vital role in the maintenance and pathogenesis of V\u03b34<jats:sup>+<\/jats:sup>\u03b3\u03b4T17 cells.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1211620","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T11:08:50Z","timestamp":1692356930000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["IL-21 is required for the maintenance and pathogenesis of murine V\u03b34+ IL-17-producing \u03b3\u03b4T cells"],"prefix":"10.3389","volume":"14","author":[{"given":"Junichi","family":"Ishikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Suto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Suga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Kageyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arifumi","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumasa","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nakajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.11.004","article-title":"The natural and the inducible: interleukin (IL)-17-producing gammadelta T cells","volume":"34","author":"Chien","year":"2013","journal-title":"Trends Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120216","article-title":"gammadelta T cells: first line of defense and beyond","volume":"32","author":"Chien","year":"2014","journal-title":"Annu Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/322836a0","article-title":"Diversity of murine gamma genes and expression in fetal and adult T lymphocytes","volume":"322","author":"Heilig","year":"1986","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.immuni.2012.06.003","article-title":"Development of interleukin-17-producing gammadelta T cells is restricted to a functional embryonic wave","volume":"37","author":"Haas","year":"2012","journal-title":"Immunity"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.06.011","article-title":"gammadelta T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response","volume":"37","author":"Zeng","year":"2012","journal-title":"Immunity"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019104159","article-title":"Littman and D. 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