Transgenic Expression of TGF-β on Thyrocytes Inhibits Development of Spontaneous Autoimmune Thyroiditis and Increases Regulatory T Cells in Thyroids of NOD.H-2h4 Mice

Abstract

Transgenic NOD.H-2h4 mice expressing TGF-β under control of the thyroglobulin promoter were generated to assess the role of TGF-β in the development of thyrocyte hyperplasia. In contrast to nontransgenic littermates, which develop lymphocytic spontaneous autoimmune thyroiditis (L-SAT), all TGF-β 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 TCRα−/− 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-γ and IFN-γ–inducible chemokines in thyroids of Tg mice. The results suggest that spontaneous autoimmune thyroiditis is inhibited in mice expressing transgenic TGF-β on thyrocytes, at least in part, because there is an increased frequency of Tregs in their thyroids.