BACKGROUND CD8+ T lymphocytes are critical mediators of neuroinflammatory diseases. Understanding the mechanisms that govern the function of this T cell population is crucial to better understanding central nervous system autoimmune disease pathology. We recently identified a novel population of highly cytotoxic c-Met-expressing CD8+ T lymphocytes and found that hepatocyte growth factor (HGF) limits effective murine cytotoxic T cell responses in cancer models. Here, we examined the role of c-Met-expressing CD8+ T cells by using a MOG35-55 T cell-mediated EAE model. METHODS Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35-55 in complete Freund's adjuvant (CFA). Peripheral and CNS inflammation was evaluated at peak disease and chronic phase, and c-Met expression by CD8 was evaluated by flow cytometry and immunofluorescence. Molecular, cellular, and killing function analysis were performed by real-time PCR, ELISA, flow cytometry, and killing assay. RESULTS In the present study, we observed that a fraction of murine effector CD8+ T cells expressed c-Met receptor (c-Met+CD8+) in an experimental autoimmune encephalitis (EAE) model. Phenotypic and functional analysis of c-Met+CD8+ T cells revealed that they recognize the encephalitogenic epitope myelin oligodendrocyte glycoprotein37-50. We demonstrated that this T cell population produces higher levels of interferon-γ and granzyme B ex vivo and that HGF directly restrains the cytolytic function of c-Met+CD8+ T cells in cell-mediated cytotoxicity reactions CONCLUSIONS: Altogether, our findings suggest that the HGF/c-Met pathway could be exploited to modulate CD8+ T cell-mediated neuroinflammation.

中文翻译：

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c-Met由高度自反应的致脑炎性CD8 +细胞表达。

背景技术CD8 + T淋巴细胞是神经炎性疾病的关键介质。了解控制该T细胞群体功能的机制对于更好地了解中枢神经系统自身免疫性疾病病理至关重要。我们最近确定了一种新型的高细胞毒性表达c-Met的CD8 + T淋巴细胞，并发现肝细胞生长因子（HGF）限制了在癌症模型中有效的鼠细胞毒性T细胞反应。在这里，我们通过使用MOG35-55 T细胞介导的EAE模型检查了表达c-Met的CD8 + T细胞的作用。方法用完全弗氏佐剂（CFA）中的髓鞘少突胶质细胞糖蛋白肽（MOG）35-55皮下免疫小鼠。在疾病高峰期和慢性期评估周围和中枢神经系统的炎症，通过流式细胞术和免疫荧光评估CD8的c-Met表达。分子，细胞和杀伤功能分析通过实时PCR，ELISA，流式细胞仪和杀伤试验进行。结果在本研究中，我们观察到一部分小鼠效应CD8 + T细胞在实验性自身免疫性脑炎（EAE）模型中表达c-Met受体（c-Met + CD8 +）。对c-Met + CD8 + T细胞的表型和功能分析表明，它们可以识别脑致病性表位髓磷脂少突胶质细胞糖蛋白37-50。我们证明该T细胞群体离体产生更高水平的干扰素-γ和颗粒酶B，HGF在细胞介导的细胞毒性反应中直接抑制c-Met + CD8 + T细胞的细胞溶解功能。结论：