TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8+CD103+ DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity.

Additional Metadata
Keywords Conditional gene targeting, Dendritic cells, EAE, Smad7, Tolerance induction
Persistent URL dx.doi.org/10.1073/pnas.1615065114, hdl.handle.net/1765/98101
Journal Proceedings of the National Academy of Sciences of the United States of America
Citation
Lukas, D. (Dominika), Yogev, N. (Nir), Kel, J.M, Regen, T. (Tommy), Mufazalov, I.A. (Ilgiz A.), Tang, Y. (Yilang), … Waisman, A. (2017). TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity. Proceedings of the National Academy of Sciences of the United States of America, 114(8), E1480–E1489. doi:10.1073/pnas.1615065114