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TGF-ß inhibitor Smad7 regulates dendritic cell-induced autoimmunity.
Lukas, Dominika; Yogev, Nir; Kel, Junda M; Regen, Tommy; Mufazalov, Ilgiz A; Tang, Yilang; Wanke, Florian; Reizis, Boris; Müller, Werner; Kurschus, Florian C; Prinz, Marco; Kleiter, Ingo; Clausen, Björn E; Waisman, Ari.
Affiliation
  • Lukas D; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  • Yogev N; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  • Kel JM; Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands.
  • Regen T; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  • Mufazalov IA; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  • Tang Y; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  • Wanke F; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  • Reizis B; Department of Pathology, New York University School of Medicine, New York, NY 10016.
  • Müller W; Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
  • Kurschus FC; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  • Prinz M; Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
  • Kleiter I; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
  • Clausen BE; Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
  • Waisman A; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany; waisman@uni-mainz.de bclausen@uni-mainz.de.
Proc Natl Acad Sci U S A ; 114(8): E1480-E1489, 2017 02 21.
Article in En | MEDLINE | ID: mdl-28167776
TGF-ß 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Dendritic Cells / Autoimmunity / Transforming Growth Factor beta / Smad7 Protein Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2017 Type: Article Affiliation country: Germany

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Dendritic Cells / Autoimmunity / Transforming Growth Factor beta / Smad7 Protein Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2017 Type: Article Affiliation country: Germany