title: Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis.
abstract: Autoreactive CD4+ T lymphocytes play a vital role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Since the discovery of T helper 17 cells, there is an ongoing debate whether T helper 1, T helper 17 or both subtypes of T lymphocytes are important for the initiation of autoimmune neuroinflammation. We examined peripheral blood CD4+ cells from patients with active and stable relapsing-remitting multiple sclerosis, and used mice with conditional deletion or over-expression of the transforming growth factor-beta inhibitor Smad7, to delineate the role of Smad7 in T cell differentiation and autoimmune neuroinflammation. We found that Smad7 is up-regulated in peripheral CD4+ cells from patients with multiple sclerosis during relapse but not remission, and that expression of Smad7 strongly correlates with T-bet, a transcription factor defining T helper 1 responses. Concordantly, mice with transgenic over-expression of Smad7 in T cells developed an enhanced disease course during experimental autoimmune encephalomyelitis, accompanied by elevated infiltration of inflammatory cells and T helper 1 responses in the central nervous system. On the contrary, mice with a T cell-specific deletion of Smad7 had reduced disease and central nervous system inflammation. Lack of Smad7 in T cells blunted T cell proliferation and T helper 1 responses in the periphery but left T helper 17 responses unaltered. Furthermore, frequencies of regulatory T cells were increased in the central nervous system of mice with a T cell-specific deletion and reduced in mice with a T cell-specific over-expression of Smad7. Downstream effects of transforming growth factor-beta on in vitro differentiation of naïve T cells to T helper 1, T helper 17 and regulatory T cell phenotypes were enhanced in T cells lacking Smad7. Finally, Smad7 was induced during T helper 1 differentiation and inhibited during T helper 17 differentiation. Taken together, the level of Smad7 in T cells determines T helper 1 polarization and regulates inflammatory cellular responses. Since a Smad7 deletion in T cells leads to immunosuppression, Smad7 may be a potential new therapeutic target in multiple sclerosis.
authors.affiliation: Department of Neurology, University Medical Centre Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany. ingo.kleiter@klinik.uni-regensburg.de
authors.forename: Ingo
authors.initials: I
authors.lastname: Kleiter
authors.forename: Jian
authors.initials: J
authors.lastname: Song
authors.forename: Dominika
authors.initials: D
authors.lastname: Lukas
authors.forename: Maruf
authors.initials: M
authors.lastname: Hasan
authors.forename: Bernhard
authors.initials: B
authors.lastname: Neumann
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Croxford
authors.forename: Xiomara
authors.initials: X
authors.lastname: Pedré
authors.forename: Nadine
authors.initials: N
authors.lastname: Hövelmeyer
authors.forename: Nir
authors.initials: N
authors.lastname: Yogev
authors.forename: Alexander
authors.initials: A
authors.lastname: Mildner
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Elena
authors.initials: E
authors.lastname: Wiese
authors.forename: Kurt
authors.initials: K
authors.lastname: Reifenberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bogdahn
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinbrecher
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051906:Smad7 Protein / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D051906:Smad7 Protein; C497807:Smad7 protein, mouse