Abstract
In multiple sclerosis, activated CD4+ T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow–derived dendritic cells (BMDCs) and that CD4+ T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4+ T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4+ T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.
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Acknowledgements
This work was supported by a Grant-in-Aid for Young Scientists (S) from the Japan Society for the Promotion of Sciences (19679007) to T.Y., and a Grant-in-Aid from Ministry of Health, Labour and Welfare to T.Y. We thank H. Hayakawa and members of the Yamashita laboratory for fruitful discussion and help.
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T.K. performed preliminary experiments for expression analysis, behavioral and histological analysis of EAE, and cytokine production, and contributed to conceiving the study. Later, R.M. took over the work and performed all experiments, with the exception of the portions indicated below. Y.N. performed EAE induction, adoptive transfer experiments, immunohistochemical analyses and spinal cord injury experiments. Y.F. performed the lymphocyte binding assay, Rap1 activity assay and cytokine analysis. M.M., J.T. and S.K. performed experiments with PBMCs. T.O. helped with irradiation experiments. M.M., T.A., J.T., M.Y., H.M. and S.K. performed experiments with autopsy samples. T.K and T.Y. conceived the project and developed the hypothesis. T.K, R.M., A.K. and T.Y. designed the experiments. A.K. and T.O. discussed the hypothesis and helped with data interpretation. T.Y. coordinated and directed the project and wrote the manuscript.
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Muramatsu, R., Kubo, T., Mori, M. et al. RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis. Nat Med 17, 488–494 (2011). https://doi.org/10.1038/nm.2321
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DOI: https://doi.org/10.1038/nm.2321
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