Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212;
J Immunol. 2013 Nov 15;191(10):4940-9. doi: 10.4049/jimmunol.1301253. Epub 2013 Oct 4.
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(-/-) 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(-/-) NOD.H2-h4 mice develop more severe ISAT than do wild-type (WT) mice, with collagen deposition (fibrosis) and low serum T4. CD28(-/-) mice have increased expression of proinflammatory cytokines IFN-γ 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(-/-) mice without increasing the total number of Tregs, suggesting that endogenous Tregs in CD28(-/-) mice are functionally ineffective. Endogenous CD28(-/-) 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(-/-) 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(-/-) 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-deficient (B(-/-)) NOD.H-2h4 mice are resistant to ISAT, but CD28(-/-)B(-/-) mice develop ISAT comparable to WT mice and have reduced numbers of Tregs compared with WT B(-/-) mice.
给予 NOD.H-2h4 小鼠饮用水中的碘化钠会导致碘加速自发性自身免疫性甲状腺炎（ISAT），甲状腺发生 T 和 B 细胞慢性炎症，并产生抗鼠甲状腺球蛋白（MTg）自身抗体。为了研究 Tregs 在 ISAT 发展中的作用，开发了 CD28(-/-) NOD.H-2h4 小鼠，其 CD4(+)Foxp3(+)调节性 T 细胞（Tregs）数量减少。CD28(-/-) NOD.H2-h4 小鼠比野生型（WT）小鼠发展出更严重的 ISAT，伴有胶原沉积（纤维化）和血清 T4 降低。CD28(-/-) 小鼠促炎细胞因子 IFN-γ 和 IL-6 表达增加，与甲状腺中单核细胞浸润和组织破坏增加一致。重要的是，从 WT 小鼠中转移纯化的 CD4(+)Foxp3(+) Tregs 可减轻 CD28(-/-) 小鼠的 ISAT 严重程度，而不增加 Tregs 的总数，表明 CD28(-/-) 小鼠中的内源性 Tregs 功能无效。与转移的 CD28(+/+) Tregs 相比，内源性 CD28(-/-) Tregs 的表面 CD27、TNFR2 p75 和糖皮质激素诱导的 TNFR 相关蛋白表达减少。尽管抗 MTg 自身抗体水平通常与 WT 小鼠的 ISAT 严重程度评分相关，但 CD28(-/-) 小鼠的抗 MTg 自身抗体反应低于 WT 小鼠。CD28(-/-) 小鼠的脾滤泡 B 细胞百分比降低，边缘区 B 细胞百分比升高，且甲状腺浸润 B 细胞数量少于 WT 小鼠。这表明 CD28 缺乏对 B 细胞具有直接和间接的影响。B 细胞缺陷（B(-/-)）NOD.H-2h4 小鼠对 ISAT 具有抗性，但 CD28(-/-)B(-/-) 小鼠发展为与 WT 小鼠相当的 ISAT，且与 WT B(-/-) 小鼠相比，Tregs 数量减少。
