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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that TLR5-deficiency led to a reduction in CD11c<jats:sup>+<\/jats:sup> DC development <jats:italic>in utero<\/jats:italic>, prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8\u03b1 co-expression, and hyper-secretion of different cytokines, both <jats:italic>in vitro<\/jats:italic> (after stimulation) and directly <jats:italic>ex vivo<\/jats:italic>. We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4<jats:sup>+<\/jats:sup> T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1333967","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T12:22:04Z","timestamp":1709122924000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model"],"prefix":"10.3389","volume":"15","author":[{"given":"James Alexander","family":"Pearson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youjia","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. 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