title: RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis.
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.
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Muramatsu
authors.forename: Takekazu
authors.initials: T
authors.lastname: Kubo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Mori
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujita
authors.forename: Tsugio
authors.initials: T
authors.lastname: Akutsu
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.forename: Junko
authors.initials: J
authors.lastname: Taniguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D055785:Gene Knockdown Techniques; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology; D009103:Multiple Sclerosis / Q000209:etiology / Q000276:immunology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D058851:GPI-Linked Proteins; C571326:MOG protein, human; D008565:Membrane Proteins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C483496:Rgma protein, mouse; C091279:neogenin