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Several auto-Ags are fundamental to disease development, suggesting T1D etiology is heterogeneous and may limit the effectiveness of Ag-specific therapies to distinct disease endotypes. Colonization factor antigen I (CFA\/I) fimbriae from<jats:italic>Escherichia coli<\/jats:italic>can inhibit autoimmune diseases in murine models by inducing bystander tolerance. To test if Ag-independent stimulation of regulatory T cells (Tregs) can prevent T1D onset, groups of NOD mice were orally treated with<jats:italic>Lactococcus lactis<\/jats:italic>(LL) expressing CFA\/I. LL-CFA\/I treatment beginning at 6 weeks of age reduced disease incidence by 50% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and increased splenic Tregs producing both IL-10 and IFN-\u03b3 8-fold (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.005) compared to LL-vehicle treated controls. To further describe the role of these Tregs in preventing T1D, protective phenotypes were examined at different time-points. LL-CFA\/I treatment suppressed splenic TNF-\u03b1<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>T cells 6-fold at 11 weeks (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.005) and promoted a distinct microbiome. At 17 weeks, IFN-\u03b3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells were suppressed 10-fold (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.005), and at 30 weeks, pancreatic Tbet<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells were suppressed (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). These results show oral delivery of modified commensal organisms, such as LL-CFA\/I, may be harnessed to restrict Th1 cell-mediated immunity and protect against T1D.<\/jats:p>","DOI":"10.1038\/s41598-020-62881-4","type":"journal-article","created":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T10:03:56Z","timestamp":1586426636000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Oral therapy with colonization factor antigen I prevents development of type 1 diabetes in Non-obese Diabetic mice"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5107-2168","authenticated-orcid":false,"given":"Andrew S.","family":"Nelson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Maddaloni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey R.","family":"Abbott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Akgul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Ohland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raad Z.","family":"Gharaibeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Jobin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2878-9296","authenticated-orcid":false,"given":"Todd M.","family":"Brusko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6572-6916","authenticated-orcid":false,"given":"David W.","family":"Pascual","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,4,9]]},"reference":[{"key":"62881_CR1","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1056\/NEJM198605223142106","volume":"314","author":"GS Eisenbarth","year":"1986","unstructured":"Eisenbarth, G. 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