CD8(+) T-Cells as Immune Regulators of Multiple Sclerosis.
CD8(+) T-Cells as Immune Regulators of Multiple Sclerosis.
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DOI：
10.3389/fimmu.2015.00619
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发表时间：
2015
影响因子：
7.3
通讯作者：
Karandikar NJ
中科院分区：
文献类型：
--
作者：
Sinha S;Boyden AW;Itani FR;Crawford MP;Karandikar NJ
绝大多数关于MS（及其动物模型EAE）免疫基础的研究主要集中在CD 4 + T细胞作为疾病的介质和调节因子。有趣的是，CD 8 + T细胞代表了人MS病变中的主要T细胞群，并且在病理部位寡克隆扩增。然而，它们在自身免疫病理过程中的作用一直是研究不足和有争议的。一些动物模型和MS患者研究支持CNS特异性CD 8 + T细胞的致病作用，而我们和其他人已经证明了这些细胞在疾病中的调节作用。在这篇综述中，我们描述了研究，研究了CD 8 + T细胞在MS和EAE中的作用，提出了致病和调节功能的证据。在我们的研究中，我们已经表明，细胞毒性/抑制性CD 8 + T细胞是CNS抗原特异性的，MHC I类限制性的，IFNγ和穿孔素依赖性的，并且能够抑制疾病。CD 8 + T细胞抑制功能的临床相关性最好通过MS复发期间缺乏其功能来描述，并且重要的是，在静止期间恢复其抑制功能。此外，具有免疫抑制功能的CD 8 + T细胞可以通过醋酸格拉替雷（GA）治疗在MS患者中治疗性诱导。与CNS特异性CD 8 + T细胞不同，这些免疫抑制性GA诱导的CD 8 + T细胞似乎是HLA-E限制性的。这些研究为自身反应性以及治疗诱导的CD 8 + T细胞在疾病改善中的作用提供了更基本的见解。这些发现的临床意义是巨大的，我们建议可以利用这种自然过程来开发有效的免疫策略。
The vast majority of studies regarding the immune basis of MS (and its animal model, EAE) have largely focused on CD4+ T-cells as mediators and regulators of disease. Interestingly, CD8+ T-cells represent the predominant T-cell population in human MS lesions and are oligoclonally expanded at the site of pathology. However, their role in the autoimmune pathologic process has been both understudied and controversial. Several animal models and MS patient studies support a pathogenic role for CNS-specific CD8+ T-cells, whereas we and others have demonstrated a regulatory role for these cells in disease. In this review, we describe studies that have investigated the role of CD8+ T-cells in MS and EAE, presenting evidence for both pathogenic and regulatory functions. In our studies, we have shown that cytotoxic/suppressor CD8+ T-cells are CNS antigen-specific, MHC class I-restricted, IFNγ- and perforin-dependent, and are able to inhibit disease. The clinical relevance for CD8+ T-cell suppressive function is best described by a lack of their function during MS relapse, and importantly, restoration of their suppressive function during quiescence. Furthermore, CD8+ T-cells with immunosuppressive functions can be therapeutically induced in MS patients by glatiramer acetate (GA) treatment. Unlike CNS-specific CD8+ T-cells, these immunosuppressive GA-induced CD8+ T-cells appear to be HLA-E restricted. These studies have provided greater fundamental insight into the role of autoreactive as well as therapeutically induced CD8+ T-cells in disease amelioration. The clinical implications for these findings are immense and we propose that this natural process can be harnessed toward the development of an effective immunotherapeutic strategy.