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: Ingo Kleiter, Jian Song, Dominika Lukas, Maruf Hasan, Bernhard Neumann, Andrew L Croxford, Xiomara Pedré, Nadine Hövelmeyer, Nir Yogev, Alexander Mildner, Marco Prinz, Elena Wiese, Kurt Reifenberg, Stefan Bittner, Heinz Wiendl, Lawrence Steinman, Christoph Becker, Ulrich Bogdahn, Markus F Neurath, Andreas Steinbrecher, Ari Waisman
• Journal: Brain : a journal of neurology (Brain) Vol. 133 Issue Pt 4 Pg. 1067-81 (Apr 2010) ISSN: 1460-2156 [Electronic] England
• PMID: 20354004 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Smad7 Protein
• Smad7 protein, mouse

Topics

• Amino Acid Sequence
• Animals
• Encephalomyelitis, Autoimmune, Experimental (immunology, metabolism, pathology)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Molecular Sequence Data
• Multiple Sclerosis (immunology, metabolism, pathology)
• Smad7 Protein (biosynthesis, deficiency, physiology)
• Th1 Cells (immunology, metabolism)