{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:18:30Z","timestamp":1791299910947,"version":"4.1.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2013,11,1]],"date-time":"2013-11-01T00:00:00Z","timestamp":1383264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>NOD.H-2h4 mice given NaI in their drinking water develop iodine-accelerated spontaneous autoimmune thyroiditis (ISAT) with chronic inflammation of the thyroid by T and B cells and production of anti-mouse thyroglobulin (MTg) autoantibody. CD28\u2212\/\u2212 NOD.H-2h4 mice, which have reduced numbers of CD4+Foxp3+ regulatory T cells (Tregs), were developed to examine the role of Tregs in ISAT development. CD28\u2212\/\u2212 NOD.H2-h4 mice develop more severe ISAT than do wild-type (WT) mice, with collagen deposition (fibrosis) and low serum T4. CD28\u2212\/\u2212 mice have increased expression of proinflammatory cytokines IFN-\u03b3 and IL-6, consistent with increased mononuclear cell infiltration and tissue destruction in thyroids. Importantly, transferring purified CD4+Foxp3+ Tregs from WT mice reduces ISAT severity in CD28\u2212\/\u2212 mice without increasing the total number of Tregs, suggesting that endogenous Tregs in CD28\u2212\/\u2212 mice are functionally ineffective. Endogenous CD28\u2212\/\u2212 Tregs have reduced surface expression of CD27, TNFR2 p75, and glucocorticoid-induced TNFR-related protein compared with transferred CD28+\/+ Tregs. Although anti-MTg autoantibody levels generally correlate with ISAT severity scores in WT mice, CD28\u2212\/\u2212 mice have lower anti-MTg autoantibody responses than do WT mice. The percentages of follicular B cells are decreased and those of marginal zone B cells are increased in spleens of CD28\u2212\/\u2212 mice, and they have fewer thyroid-infiltrating B cells than do WT mice. This suggests that CD28 deficiency has direct and indirect effects on the B cell compartment. B cell\u2013deficient (B\u2212\/\u2212) NOD.H-2h4 mice are resistant to ISAT, but CD28\u2212\/\u2212B\u2212\/\u2212 mice develop ISAT comparable to WT mice and have reduced numbers of Tregs compared with WT B\u2212\/\u2212 mice.<\/jats:p>","DOI":"10.4049\/jimmunol.1301253","type":"journal-article","created":{"date-parts":[[2013,10,5]],"date-time":"2013-10-05T03:54:05Z","timestamp":1380945245000},"page":"4940-4949","source":"Crossref","is-referenced-by-count":24,"title":["Reduced Effectiveness of CD4+Foxp3+ Regulatory T Cells in CD28-Deficient NOD.H-2h4 Mice Leads to Increased Severity of Spontaneous Autoimmune Thyroiditis"],"prefix":"10.1093","volume":"191","author":[{"given":"Jason S","family":"Ellis","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Missouri School of Medicine , Columbia, MO 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Hee","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Missouri School of Medicine , Columbia, MO 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habib","family":"Zaghouani","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine , Columbia, MO 65212"},{"name":"Department of Child Health, University of Missouri School of Medicine , Columbia, MO 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Braley-Mullen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Missouri School of Medicine , Columbia, MO 65212"},{"name":"Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine , Columbia, MO 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,11,15]]},"reference":[{"key":"2025032405554023000_r1","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1006\/jaut.1999.0272","article-title":"Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice","volume":"12","author":"Braley-Mullen","year":"1999","journal-title":"J. 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