Transforming Growth Factor-β Has Contrasting Effects in the Presence or Absence of Exogenous Interleukin-12 on the In Vitro Activation of Cells That Transfer Experimental Autoimmune Thyroiditis

Mouse thyroglobulin (MuTg)-sensitized spleen cells activated in vitro with MuTg induce experimental autoimmune thyroiditis (EAT) in recipient mice with a thyroid infiltrate consisting primarily of lymphocytes. A more severe and histologically distinct granulomatous form of EAT (G-EAT) is induced when donor cells are activated with MuTg together with anti-interferon-γ (IFN-γ), anti-interleukin-2 receptor (IL-2R) monoclonal antibody (mAb), and IL-12. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that can both suppress and exacerbate autoimmune diseases and often has inhibitory effects on lymphocytes. To determine if TGF-β could modulate the in vitro activation of effector cells for G-EAT, TGF-β was added to cultures of MuTg-sensitized donor spleen cells together with MuTg. Cells activated in the presence of 2 ng/ml TGF-β induced moderately severe G-EAT in recipient mice. G-EAT induced by cells activated in the presence of TGF-β was histologically similar but less severe than the G-EAT induced by cells activated in the presence of IL-12. IL-12 and TGF-β modulate the activation of G-EAT effector cells by distinct mechanisms, as cells activated by TGF-β could induce G-EAT in the presence of anti-IL-12, and TGF-β inhibited the effects of IL-12 on EAT effector cells. TGF-β exerted its activity during the first 24 h of the 72-h culture, whereas IL-12 functioned primarily during the final 24 h of culture. These results indicate that thyroid lesions with granulomatous histopathology can be induced by both IL-12-dependent and IL-12-independent mechanisms, and TGF-β can exert both positive and negative effects on the effector cells for G-EAT.