RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis
RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis
复制标题
DOI：
10.1038/nm.2321
复制
发表时间：
2011-04-01
期刊：
影响因子：
82.9
通讯作者：
Yamashita, Toshihide
中科院分区：
文献类型：
--
作者：
Muramatsu, Rieko;Kubo, Takekazu;Yamashita, Toshihide
在多发性硬化症中，激活的 CD4(+) T 细胞会在大脑和脊髓中引发免疫反应，导致脱髓鞘、变性和进行性瘫痪。排斥引导分子-a (RGMa) 是一种轴突引导分子，在视觉系统和神经管闭合中发挥作用。我们的研究表明，RGMa 在骨髓源性树突状细胞 (BMDC) 中表达，并且 CD4(+) T 细胞表达 RGMa 的受体 neogenin。 RGMa与CD4(+) T细胞的结合导致小GTPase Rap1的激活并增加T细胞与细胞内粘附分子-1(ICAM-1)的粘附。 RGMa 中和抗体可减轻小鼠髓磷脂少突胶质细胞糖蛋白 (MOG) 诱导的实验性自身免疫性脑脊髓炎 (EAE) 的临床症状，并减少炎症细胞侵入中枢神经系统。 MOG 脉冲的 BMDC 中 RGMa 的沉默降低了其在过继转移至幼稚 C57BL/6 小鼠后诱导 EAE 的能力。从用 RGMa 特异性抗体处理的小鼠中分离的 CD4(+) T 细胞显示增殖反应减弱，干扰素 γ (IFN-γ)、白细胞介素 2 (IL-2)、IL-4 和 IL-17 分泌减少。将多发性硬化症患者的 PBMC 与 RGMa 特异性抗体一起孵育可降低增殖反应和促炎细胞因子的表达。这些结果表明 RGMa 特异性抗体可抑制 T 细胞反应，并表明 RGMa 可能成为治疗多发性硬化症的有希望的分子靶点。
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-gamma (IFN-gamma), 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.