Transforming growth factor-beta has contrasting effects in the presence orabsence 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 wit h a thyroid infiltrate consisting primarily of lymphocytes. A more severe a nd histologically distinct granulomatous form of EAT (G-EAT) is induced whe n donor cells are activated with MuTg together with anti-interferon-gamma ( IFN-gamma), anti-interleukin-2 receptor (IL-2R) monoclonal antibody (mAb), and IL-12. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that can both suppress and exacerbate autoimmune diseases and ofte n has inhibitory effects on lymphocytes. To determine if TGF-beta could mod ulate the in vitro activation of effector cells for G-EAT, TGF-beta was add ed to cultures of MuTg-sensitized donor spleen cells together with MuTg. Ce lls activated in the presence of 2 ng/ml TGF-beta induced moderately severe G-EAT in recipient mice. G-EAT induced by cells activated in the presence of TGF-beta was histologically similar but less severe than the G-EAT induc ed by cells activated in the presence of IL-12. IL-12 and TGF-beta modulate the activation of G-EAT effector cells by distinct mechanisms, as cells ac tivated by TGF-beta could induce G-EAT in the presence of anti-IL-12, and T GF-beta inhibited the effects of IL-12 on EAT effector cells. TGF-beta exer ted its activity during the first 24 h of the 72-h culture, whereas IL-12 f unctioned primarily during the final 24 h of culture. These results indicat e that thyroid lesions with granulomatous histopathology can be induced by both IL-12-dependent and IL-12-independent mechanisms, and TGF-beta can exe rt both positive and negative effects on the effector cells for G-EAT.