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The aims of our study were to explore the diabetes\u2010preventive effect in NOD mice and the potential mechanisms of an optimized co\u2010expression DNA vaccine containing GAD65 fragment gene with the IL\u201010 gene (SGAD65<jats:sub>190\u2010315<\/jats:sub>\/IL\u201010).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Female NOD mice at the age of 3\u20134\u00a0weeks old were randomly divided into two groups and received intra\u2010muscular injection of either blank pBudCE4.l vector (<jats:italic>n<\/jats:italic>\u2009=\u200934) or pBudCE4.l carrying the SGAD65<jats:sub>190\u2010315<\/jats:sub>\/IL\u201010 (<jats:italic>n<\/jats:italic>\u2009=\u200932). The incidence of diabetes was monitored up to 30\u00a0weeks of age. The severity of insulitis, apoptosis rate of \u03b2 cells and relevant mechanisms were examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Administration with SGAD65<jats:sub>190\u2010315<\/jats:sub>\/IL\u201010 blocked the onset of autoimmune diabetes in NOD mice, significantly suppressed islet inflammation, inhibited the apoptosis of islet \u03b2 cells, induced immune tolerance to autoantigen GAD65 and proinsulin and shifted the Th1\/Th2 balance towards Th2. More importantly, the frequencies of CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Foxp3<jats:sup>+<\/jats:sup> regulatory T cells (Tregs) in the spleen and pancreatic lymph nodes in vaccine\u2010immunized mice were significantly increased, and these Tregs were GAD65\u2010reactive. In addition, Treg depletion by anti\u2010CD25 mAb administration abolished the protective effects of SGAD65<jats:sub>190\u2010315<\/jats:sub>\/IL\u201010 on diabetes and insulitis. Moreover, depletion of CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup> T cells using magnetic\u2010activated cell sorting impaired the protective effect of SGAD65<jats:sub>190\u2010315<\/jats:sub>\/IL\u201010 vaccination on adoptive transfer of diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data suggested that SGAD65<jats:sub>190\u2010315<\/jats:sub>\/IL\u201010 DNA vaccine had protective effects on T1D by upregulating autoantigen\u2010reactive Tregs. Our findings may provide a novel preventive therapy for T1D. Copyright \u00a9 2016 John Wiley &amp; Sons, Ltd.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dmrr.2780","type":"journal-article","created":{"date-parts":[[2016,1,21]],"date-time":"2016-01-21T15:31:16Z","timestamp":1453390276000},"page":"522-533","source":"Crossref","is-referenced-by-count":27,"title":["Vaccination with a co\u2010expression DNA plasmid containing GAD65 fragment gene and IL\u201010 gene induces regulatory CD4<sup>+<\/sup> T cells that prevent experimental autoimmune diabetes"],"prefix":"10.1002","volume":"32","author":[{"given":"Xinyuan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Metabolism and Endocrinology, Second Xiangya Hospital Central South University, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases  Changsha Hunan China 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