Chuanshan Zhang1,2, Renyong Lin3, Zhide Li1, Shuting Yang1, Xiaojuan Bi3, Hui Wang3, Abudusalamu Aini1, Ning Zhang1, Abuduaini Abulizi1, Cheng Sun4, Liang Li3, Zhibin Zhao5, Rongde Qin6, Xiaohong Li6, Liang Li3, Tuerganaili Aji7, Yingmei Shao7, Dominique A Vuitton8, Zhigang Tian4, Hao Wen1. 1. 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. 2. Basic Medical College, Xinjiang Medical University, Urumqi, China. 3. Xinjiang Key Laboratory of Echinococcosis, Clinical Medicine Institute, WHO Collaborating Centre on Prevention and Case Management of Echinococcosis, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China. 4. Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Diseases, University of Science and Technology of China, Hefei, China. 5. Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China. 6. Department of Nuclear Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China. 7. Department of Hepatic Hydatid and Hepatobiliary Surgery, Digestive and Vascular Surgery Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China. 8. WHO-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, Department of Parasitology, University Hospital, University Bourgogne Franche-Comté, Besançon, France.
Abstract
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.
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-infectedmice. Importantly, in vivo blocking TIGIT prevented T-cell exhaustion and inhibited disease progression in E. multilocularis-infectedmice. 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.