Verginis Panayotis, Li Haiyan S, Carayanniotis George
Divisions of Endocrinology and Basic Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
J Immunol. 2005 Jun 1;174(11):7433-9. doi: 10.4049/jimmunol.174.11.7433.
Ex vivo treatment of bone marrow-derived dendritic cells (DCs) with TNF-alpha has been previously shown to induce partial maturation of DCs that are able to suppress autoimmunity. In this study, we demonstrate that i.v. administration of TNF-alpha-treated, semimature DCs pulsed with thyrogloblin (Tg), but not with OVA Ag, inhibits the subsequent development of Tg-induced experimental autoimmune thyroiditis (EAT) in CBA/J mice. This protocol activates CD4(+)CD25(+) T cells in vivo, which secrete IL-10 upon specific recognition of Tg in vitro and express regulatory T cell (Treg)-associated markers such as glucocorticoid-induced TNFR, CTLA-4, and Foxp3. These CD4(+)CD25(+) Treg cells suppressed the proliferation and cytokine release of Tg-specific, CD4(+)CD25(-) effector cells in vitro, in an IL-10-independent, cell contact-dependent manner. Prior adoptive transfer of the same CD4(+)CD25(+) Treg cells into CBA/J hosts suppressed Tg-induced EAT. These results demonstrate that the tolerogenic potential of Tg-pulsed, semimature DCs in EAT is likely to be mediated through the selective activation of Tg-specific CD4(+)CD25(+) Treg cells and provide new insights for the study of Ag-specific immunoregulation of autoimmune diseases.
先前的研究表明，用肿瘤坏死因子-α（TNF-α）对骨髓来源的树突状细胞（DCs）进行体外处理可诱导DCs部分成熟，从而能够抑制自身免疫。在本研究中，我们证明，静脉注射用甲状腺球蛋白（Tg）而非卵清蛋白（OVA）抗原脉冲处理的TNF-α处理的半成熟DCs，可抑制CBA/J小鼠中随后发生的Tg诱导的实验性自身免疫性甲状腺炎（EAT）。该方案在体内激活CD4(+)CD25(+) T细胞，这些细胞在体外特异性识别Tg时分泌白细胞介素-10（IL-10），并表达调节性T细胞（Treg）相关标志物，如糖皮质激素诱导的肿瘤坏死因子受体（TNFR）、细胞毒性T淋巴细胞相关抗原4（CTLA-4）和叉头框蛋白3（Foxp3）。这些CD4(+)CD25(+) Treg细胞以不依赖IL-10、依赖细胞接触的方式在体外抑制Tg特异性CD4(+)CD25(-)效应细胞的增殖和细胞因子释放。事先将相同的CD4(+)CD25(+) Treg细胞过继转移到CBA/J宿主中可抑制Tg诱导的EAT。这些结果表明，在EAT中，用Tg脉冲处理的半成熟DCs的致耐受性潜力可能是通过选择性激活Tg特异性CD4(+)CD25(+) Treg细胞介导的，并为自身免疫性疾病的抗原特异性免疫调节研究提供了新的见解。
