Research Service, Department of Veterans Affairs, University of Missouri School of Medicine, Columbia, MO 65212, USA.
J Immunol. 2010 May 1;184(9):5352-9. doi: 10.4049/jimmunol.0903620. Epub 2010 Mar 24.
Transgenic NOD.H-2h4 mice expressing TGF-beta under control of the thyroglobulin promoter were generated to assess the role of TGF-beta in the development of thyrocyte hyperplasia. In contrast to nontransgenic littermates, which develop lymphocytic spontaneous autoimmune thyroiditis (L-SAT), all TGF-beta transgenic (Tg) mice given NaI water for 2-7 mo developed thyroid lesions characterized by severe thyroid epithelial cell hyperplasia and proliferation, with fibrosis and less lymphocyte infiltration than in nontransgenic mice. Most Tg mice produced less anti-mouse thyroglobulin autoantibody than did wild type (WT) mice. T cells from Tg and WT mice were equivalent in their ability to induce L-SAT after transfer to SCID or TCRalpha(-/-) mice. WT lymphocytes could transfer experimental autoimmune thyroiditis or L-SAT to Tg mice, indicating that the transgenic environment did not prevent migration of lymphocytes to the thyroid. Thyroids of Tg mice had higher frequencies of Foxp3(+) regulatory T cells (Tregs) compared with nontransgenic WT mice. Transient depletion of Tregs by anti-CD25 resulted in increased infiltration of inflammatory cells into thyroids of transgenic mice. Treg depletion also resulted in increased anti-mouse thyroglobulin autoantibody responses and increased expression of IFN-gamma and IFN-gamma-inducible chemokines in thyroids of Tg mice. The results suggest that spontaneous autoimmune thyroiditis is inhibited in mice expressing transgenic TGF-beta on thyrocytes, at least in part, because there is an increased frequency of Tregs in their thyroids.
转染 TGF-β的 NOD.H-2h4 小鼠在甲状腺球蛋白启动子的控制下表达 TGF-β，用于评估 TGF-β在甲状腺细胞增生发展中的作用。与未转基因的同窝仔鼠（其发展为淋巴细胞自发性自身免疫性甲状腺炎[L-SAT]）不同，所有给予碘酸钠水的 TGF-β转基因（Tg）小鼠在 2-7 个月后均发展为甲状腺病变，其特征为严重的甲状腺上皮细胞增生和增殖，纤维化程度较未转基因小鼠低，淋巴细胞浸润程度较低。与野生型（WT）小鼠相比，大多数 Tg 小鼠产生的抗鼠甲状腺球蛋白自身抗体较少。从 Tg 和 WT 小鼠分离的 T 细胞在转移到 SCID 或 TCRalpha(-/-)小鼠后，诱导 L-SAT 的能力相当。WT 淋巴细胞可以将实验性自身免疫性甲状腺炎或 L-SAT 转移到 Tg 小鼠，表明转基因环境并未阻止淋巴细胞向甲状腺的迁移。与未转基因 WT 小鼠相比，Tg 小鼠的甲状腺中 Foxp3(+)调节性 T 细胞（Tregs）的频率更高。用抗 CD25 短暂耗尽 Tregs 会导致炎症细胞更多地浸润转基因小鼠的甲状腺。Treg 耗竭还会导致 Tg 小鼠的抗鼠甲状腺球蛋白自身抗体反应增加，并导致 TGF-β转基因小鼠甲状腺中 IFN-γ和 IFN-γ诱导的趋化因子表达增加。这些结果表明，在甲状腺细胞中表达转基因 TGF-β的小鼠中，自发性自身免疫性甲状腺炎受到抑制，至少部分原因是其甲状腺中 Tregs 的频率增加。
