Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model
Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model
复制标题
小鼠模型中肺泡包虫病患者 T 细胞的免疫衰竭及其通过阻断检查点受体 TIGIT 的逆转
DOI：
10.1002/hep.30896
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发表时间：
2020-01-24
期刊：
影响因子：
13.5
通讯作者：
Wen, Hao
中科院分区：
文献类型：
--
作者：
Zhang, Chuanshan;Lin, Renyong;Wen, Hao
多房棘球绦虫感染是一个严重的全球性健康问题，它导致泡状棘球蚴病（AE），一种主要位于肝脏并能够扩散到任何器官的肿瘤样疾病。到目前为止，很少有研究探讨T细胞耗竭如何有助于寄生虫逃避免疫攻击以及如何逆转。方法和结果在这项研究中，我们发现肝T细胞免疫受体与免疫球蛋白和免疫受体酪氨酸基序抑制域（TIGIT）的表达显着增强，并与病变活动性在AE患者呈正相关。肝脏浸润性T细胞和血液T细胞中的高TIGIT表达与它们的功能衰竭相关，并且其配体CD 155由浸润性淋巴细胞周围的肝细胞高度表达。在使用人血T细胞和肝细胞系HL-7702的共培养实验中，CD 155诱导TIGIT（+）T细胞的功能损害，并且用TIGIT抗体的体外阻断恢复了AE患者的T细胞的功能。在E.多房感染的小鼠。重要的是，体内阻断TIGIT可防止E.多房感染的小鼠。从机制上讲，抗TIGIT诱导的小鼠寄生虫生长消退完全需要CD 4（+）T细胞，部分需要CD 8（+）T细胞。结论E.多房性脑膜炎可以通过抑制性受体TIGIT诱导T细胞耗竭，并且阻断该检查点可以逆转T细胞的功能损伤，并代表针对AE的免疫治疗的可能方法。
Background and Aims The cestode Echinococcus multilocularis infection, a serious health problem worldwide, causes alveolar echinococcosis (AE), a tumor-like disease predominantly located in the liver and able to spread to any organs. Until now, there have been few studies that explore how T-cell exhaustion contributes to the parasite's escape from immune attack and how it might be reversed. Approach and Results In this study, we found that liver T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression was significantly enhanced and positively correlated with lesion activity in AE patients. High TIGIT expression in both liver-infiltrating and blood T cells was associated with their functional exhaustion, and its ligand CD155 was highly expressed by hepatocytes surrounding the infiltrating lymphocytes. In co-culture experiments using human blood T cells and hepatic cell line HL-7702, CD155 induced functional impairment of TIGIT(+) T cells, and in vitro blockade with TIGIT antibody restored the function of AE patients' T cells. Similar TIGIT-related functional exhaustion of hepatic T cells and an abundant CD155 expression on hepatocytes were observed in E. multilocularis-infected mice. Importantly, in vivo blocking TIGIT prevented T-cell exhaustion and inhibited disease progression in E. multilocularis-infected mice. Mechanistically, CD4(+) T cells were totally and CD8(+) T cells partially required for anti-TIGIT-induced regression of parasite growth in mice. Conclusions This study demonstrates that E. multilocularis can induce T-cell exhaustion through inhibitory receptor TIGIT, and that blocking this checkpoint may reverse the functional impairment of T cells and represent a possible approach to immunotherapy against AE.