State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Basic Medical College, Xinjiang Medical University, Urumqi, China.
Hepatology. 2020 Apr;71(4):1297-1315. doi: 10.1002/hep.30896. Epub 2020 Jan 24.
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.
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.
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.
绦虫多房棘球蚴感染是一种严重的全球性健康问题，可引起泡型包虫病（AE），这是一种主要发生在肝脏的肿瘤样疾病，能够扩散到任何器官。到目前为止，很少有研究探讨 T 细胞耗竭如何帮助寄生虫逃避免疫攻击，以及如何逆转这种情况。
在这项研究中，我们发现 AE 患者肝 T 细胞免疫受体酪氨酸抑制基序（TIGIT）的表达明显增强，并与病变活性呈正相关。肝浸润和血 T 细胞中高 TIGIT 表达与它们的功能耗竭有关，其配体 CD155 在浸润淋巴细胞周围的肝细胞中高度表达。在使用人血 T 细胞和肝细胞系 HL-7702 的共培养实验中，CD155 诱导 TIGIT T 细胞功能障碍，体外阻断 TIGIT 抗体恢复 AE 患者 T 细胞的功能。在多房棘球蚴感染的小鼠中，观察到肝 T 细胞的类似 TIGIT 相关功能耗竭和肝细胞上丰富的 CD155 表达。重要的是，体内阻断 TIGIT 可防止 T 细胞耗竭并抑制多房棘球蚴感染小鼠的疾病进展。在机制上，CD4 T 细胞完全和 CD8 T 细胞部分需要抗 TIGIT 诱导的寄生虫生长消退。
这项研究表明，多房棘球绦虫可以通过抑制性受体 TIGIT 诱导 T 细胞耗竭，阻断该检查点可能逆转 T 细胞的功能障碍，代表针对 AE 的免疫治疗的一种可能方法。
