TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity.
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.
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Dominika
D
Lukas
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Nir
N
Yogev
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands.
Junda M
JM
Kel
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Tommy
T
Regen
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Ilgiz A
0000-0001-9332-0131
IA
Mufazalov
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Yilang
Y
Tang
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Florian
F
Wanke
Department of Pathology, New York University School of Medicine, New York, NY 10016.
Boris
B
Reizis
Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
Werner
0000-0002-1297-9725
W
Müller
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Florian C
FC
Kurschus
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
Marco
M
Prinz
Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
Ingo
I
Kleiter
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany; waisman@uni-mainz.de bclausen@uni-mainz.de.|Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands.
Björn E
0000-0002-2484-7842
BE
Clausen
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany; waisman@uni-mainz.de bclausen@uni-mainz.de.
Ari
A
Waisman
D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology; D051906:Smad7 Protein / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
D050976:Basic-Leucine Zipper Transcription Factors; D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050835:Interferon Regulatory Factors; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D000099185:Interferon Regulatory Factor-8; C497807:Smad7 protein, mouse
EAE; Smad7; conditional gene targeting; dendritic cells; tolerance induction