T-cell intrinsic Smad7 determines Th1/Th17 differentiation and susceptibility to autoimmune encephalomyelitis

Background: T cells play an important role in the pathogenesis of multiple sclerosis and its model disease experimental autoimmune encephalomyelitis (EAE). The transforming growth factor (TGF)-β is a cytokine of great importance for T cell differentiation, proliferation and survival. While blocking T helper (Th)1 and Th2 differentiation, TGF-β is crucial for the generation of T regulatory (Treg) and Th17 cells.

Objective: To investigate the role of Smad7, the intracellular inhibitor of TGF-β signalling, in T cell differentiation and in autoimmune inflammation of the CNS.

Methods: We used conditional gene targeting to generate mice with a specific deletion of Smad7 in T cells. We analyzed T cell differentiation in vitro and in vivo after induction of EAE with MOG(35–55) peptide. Wild type mice and mice with T cell specific overexpression of Smad7 served as controls.

Results: The steady state analysis of mice lacking Smad7 in T cells showed normal T cell development with decreased frequencies of activated T cells. When stimulated in vitro under differentiation conditions, Smad7-deficient T cells showed an increase in Treg and Th17 differentiation, whereas Th1 differentiation was strongly inhibited. Mice lacking Smad7 in T cells were partially resistant to the induction of EAE and exhibited less inflammation in the CNS. Depletion of Tregs in mice with Smad7-deficient T cells partially restored clinical development of autoimmune neuroinflammation. In contrast, mice with a transgenic overexpression of Smad7 in T cells showed a significantly enhanced EAE disease course and Th1 response, despite the lack of Th17 differentiation and infiltration in the CNS. Importantly, we have shown that systemic inhibition of Smad7 with specific antisense oligonucleotides equally suppressed EAE in wild type mice.

Conclusion: We postulate that Smad7 controls Th1 and Th17 lineage commitment decisions, and that T cells lacking Smad7 are more sensitive to TGF-β signalling. Increased Smad7 expression in T cells aggravates EAE and Th1 responses despite reduced Th17 differentiation. Lack of Smad7 in T cells ameliorates EAE and reduces Th1 effector mechanisms. Targeting of Smad7 might therefore be a therapeutic approach for T cell-mediated autoimmune diseases of the CNS.