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Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis
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 im...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850583/ https://www.ncbi.nlm.nih.gov/pubmed/20354004 http://dx.doi.org/10.1093/brain/awq039 |
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author | Kleiter, Ingo Song, Jian Lukas, Dominika Hasan, Maruf Neumann, Bernhard Croxford, Andrew L. Pedré, Xiomara Hövelmeyer, Nadine Yogev, Nir Mildner, Alexander Prinz, Marco Wiese, Elena Reifenberg, Kurt Bittner, Stefan Wiendl, Heinz Steinman, Lawrence Becker, Christoph Bogdahn, Ulrich Neurath, Markus F. Steinbrecher, Andreas Waisman, Ari |
author_facet | Kleiter, Ingo Song, Jian Lukas, Dominika Hasan, Maruf Neumann, Bernhard Croxford, Andrew L. Pedré, Xiomara Hövelmeyer, Nadine Yogev, Nir Mildner, Alexander Prinz, Marco Wiese, Elena Reifenberg, Kurt Bittner, Stefan Wiendl, Heinz Steinman, Lawrence Becker, Christoph Bogdahn, Ulrich Neurath, Markus F. Steinbrecher, Andreas Waisman, Ari |
author_sort | Kleiter, Ingo |
collection | PubMed |
description | 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-β 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-β 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. |
format | Text |
id | pubmed-2850583 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-28505832010-04-08 Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis Kleiter, Ingo Song, Jian Lukas, Dominika Hasan, Maruf Neumann, Bernhard Croxford, Andrew L. Pedré, Xiomara Hövelmeyer, Nadine Yogev, Nir Mildner, Alexander Prinz, Marco Wiese, Elena Reifenberg, Kurt Bittner, Stefan Wiendl, Heinz Steinman, Lawrence Becker, Christoph Bogdahn, Ulrich Neurath, Markus F. Steinbrecher, Andreas Waisman, Ari Brain Original Articles 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-β 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-β 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. Oxford University Press 2010-04 2010-03-30 /pmc/articles/PMC2850583/ /pubmed/20354004 http://dx.doi.org/10.1093/brain/awq039 Text en © The Author(s) 2010. Published by Oxford University Press on behalf of Brain. http://creativecommons.org/licenses/by-nc/2.5 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Kleiter, Ingo Song, Jian Lukas, Dominika Hasan, Maruf Neumann, Bernhard Croxford, Andrew L. Pedré, Xiomara Hövelmeyer, Nadine Yogev, Nir Mildner, Alexander Prinz, Marco Wiese, Elena Reifenberg, Kurt Bittner, Stefan Wiendl, Heinz Steinman, Lawrence Becker, Christoph Bogdahn, Ulrich Neurath, Markus F. Steinbrecher, Andreas Waisman, Ari Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis |
title | Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis |
title_full | Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis |
title_fullStr | Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis |
title_full_unstemmed | Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis |
title_short | Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis |
title_sort | smad7 in t cells drives t helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850583/ https://www.ncbi.nlm.nih.gov/pubmed/20354004 http://dx.doi.org/10.1093/brain/awq039 |
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