多发性硬化抗原特异性CD8+记忆性T细胞亚群的免疫学特征及其作用机制

It is previously considered that CD4+ T cells play a crucial role in pathogenesis of multiple sclerosis (MS)，but currently accumulating evidences indicate that CD8+ T cells are also involved as one of the MS-related effector cells. Three CD8+ memory T cells subsets, including central memory T cell (TCM), effector memory T cell (TEM) and terminally differentiated TEM (TEMRA)，and a newly-found cell subset, tissue-resident memory T cell (TRM) have an important role in autoimmunity. On the other hands, PD-1/Tim-3 pathway has been found to act as a strong negative regulator for T cells function, and is enriched in CD8+ TCM, probably predominantly involving in the immunomodulation of CD8+ memory T cells. We previously found that MS patients showed a dysregulated blood CD8+ memory T cells subsets in early stage, but their exact biological effect and action mechanisms remains elusive. Hence, in this study we examine the frequency and cytokine secretion of antigen-specific CD8+ memory T cell subsets in MS patients. Furthermore, in combination with the influence of co-inhibitory molecules, PD-1 and Tim-3 agonist antibody, this study paves the way for a pathway-directed treatment against early MS.

以往认为CD4+T细胞在多发性硬化（MS）的发病机制中起关键作用，现今证据表明CD8+T细胞亦是此病的主要效应细胞，其记忆性T细胞亚群，包括中心记忆性、效应记忆性、终末效应记忆性和组织定居记忆性T细胞，在自身免疫应答中均发挥重要作用。另一方面，Tim-3/PD-1通路被证实可强效负向调节CD8+T细胞功能，可能参与其记忆性T细胞的调控。我们以往发现MS早期存在外周血CD8+记忆性T细胞亚群的失调，但其确切机制尚不明。因此本课题首先分析不同亚型MS患者外周血、脑脊液髓鞘抗原特异性CD8+记忆性T细胞亚群数量及其细胞因子表达，并结合PD-1和Tim-3对上述细胞亚群功能的影响，进而为今后开展MS早期针对性治疗提供可靠的依据。

以往认为CD4+T细胞在多发性硬化（MS）的发病机制中起关键作用，现今证据表明CD8+T细胞亦是此病的主要效应细胞，其记忆性T细胞亚群，包括中心记忆性、效应记忆性、终末效应记忆性和组织定居记忆性T细胞，在自身免疫应答中均发挥重要作用。另一方面，Tim-3/PD-1通路被证实可强效负向调节CD8+T细胞功能，可能参与其记忆性T细胞的调控。我们以往发现MS早期存在外周血CD8+记忆性T细胞亚群的失调，但其确切机制尚不明。因此本课题首先分析不同亚型MS患者外周血、脑脊液髓鞘抗原特异性CD8+记忆性T细胞亚群数量及其细胞因子表达。初步结果表明：MS患者外周血抗原特异性记忆性T细胞亚群数量较健康对照组明显升高，同时也存在相应的效应性细胞因子检测水平升高，提示其参与了疾病的发生发展过程，尤其是TEM亚群，并结合PD-1和Tim-3对上述细胞亚群功能的影响，进而为今后开展MS早期针对性治疗提供可靠的依据。

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