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Immunol."],"abstract":"<jats:p>The transforming growth factor receptor III (T\u03b2RIII) is commonly recognized as a co-receptor that promotes the binding of TGF\u03b2 family ligands to type I and type II receptors. Within the immune system, T\u03b2RIII regulates T cell development in the thymus and is differentially expressed through activation; however, its function in mature T cells is unclear. To begin addressing this question, we developed a conditional knock-out mouse with restricted T\u03b2RIII deletion in mature T cells, necessary because genomic deletion of T\u03b2RIII results in perinatal mortality. We determined that T\u03b2RIII null mice developed more severe autoimmune central nervous neuroinflammatory disease after immunization with myelin oligodendrocyte peptide (MOG<jats:sub>35-55<\/jats:sub>) than wild-type littermates. The increase in disease severity in T\u03b2RIII null mice was associated with expanded numbers of CNS infiltrating IFN\u03b3<jats:sup>+<\/jats:sup> CD4<jats:sup>+<\/jats:sup> T cells and cells that co-express both IFN\u03b3 and IL-17 (IFN\u03b3<jats:sup>+<\/jats:sup>\/IL-17<jats:sup>+<\/jats:sup>), but not IL-17 alone expressing CD4 T cells compared to <jats:italic>Tgfbr3<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> wild-type controls. This led us to speculate that T\u03b2RIII may be involved in regulating conversion of encephalitogenic Th17 to Th1. To directly address this, we generated encephalitogenic Th17 and Th1 cells from wild type and T\u03b2RIII null mice for passive transfer of EAE into na\u00efve mice. Remarkably, Th17 encephalitogenic T cells from T\u03b2RIII null induced EAE of much greater severity and earlier in onset than those from wild-type mice. The severity of EAE induced by encephalitogenic wild-type and <jats:italic>Tgfbr3<jats:sup>fl\/fl<\/jats:sup>.dLcKCre<\/jats:italic> Th1 cells were similar. Moreover, <jats:italic>in vitro<\/jats:italic> restimulation of <jats:italic>in vivo<\/jats:italic> primed <jats:italic>Tgfbr3<jats:sup>fl\/fl<\/jats:sup>.dLcKCre<\/jats:italic> T cells, under Th17 but not Th1 polarizing conditions, resulted in a significant increase of IFN\u03b3<jats:sup>+<\/jats:sup> T cells. Altogether, our data indicate that T\u03b2RIII is a coreceptor that functions as a key checkpoint in controlling the pathogenicity of autoreactive T cells in neuroinflammation probably through regulating plasticity of Th17 T cells into pathogenic Th1 cells. Importantly, this is the first demonstration that T\u03b2RIII has an intrinsic role in T cells.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1088039","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T09:45:40Z","timestamp":1675763140000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Transforming growth factor receptor III (Betaglycan) regulates the generation of pathogenic Th17 cells in EAE"],"prefix":"10.3389","volume":"14","author":[{"given":"Samuel J.","family":"Duesman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Ortega-Francisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana","family":"Olguin-Alor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naray 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