MURAMATSU Rieko, YAMASHITA Toshihide ≪Molecular Neuroscience≫ “RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis”
2011-3-21
Publish Nature Medicine 17, 488-494(2011)
In multiple sclerosis, activated CD4+ T cells initiate an immune in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that plays 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 naïve C57BL/6 mice CD4+ T cells isolated from mice treated with an anti-RGMa antibody showed diminished proliferative responses and reduced interferon-g (IFN-g), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an anti-RGMa antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results show that an anti-RGMa antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.
