Kleiter, Ingo and Song, Jian and Lukas, Dominika and Hasan, Maruf and Neumann, Bernhard and Croxford, Andrew L. and Pedre, Xiomara and Hoevelmeyer, Nadine and Yogev, Nir and Mildner, Alexander and Prinz, Marco and Wiese, Elena and Reifenberg, Kurt and Bittner, Stefan and Wiendl, Heinz and Steinman, Lawrence and Becker, Christoph and Bogdahn, Ulrich and Neurath, Markus F. and Steinbrecher, Andreas and Waisman, Ari (2010) Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis. BRAIN, 133. pp. 1067-1081. ISSN 0006-8950,
Full text not available from this repository. (Request a copy)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 naive 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CENTRAL-NERVOUS-SYSTEM; I INTERFERON SIGNATURE; PERIPHERAL-BLOOD CELLS; TGF-BETA; IMMUNE-RESPONSES; CUTTING EDGE; TRANSCRIPTION FACTOR; MONONUCLEAR-CELLS; DENDRITIC CELLS; EXPRESSION; EAE; multiple sclerosis; immune regulation; T cell responses; T helper 1 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Aug 2020 08:41 |
| Last Modified: | 03 Aug 2020 08:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/24831 |
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