Involvement of TIGIT in Natural Killer Cell Exhaustion and Immune Escape in Patients and Mouse Model With Liver Echinococcus multilocularis Infection

Chuanshan Zhang^#^{1

2}, Hui Wang^#^{1

2}, Jing Li^#², Xinling Hou^{1

2}, Linghui Li¹, Wei Wang^{1

2}, Yang Shi^{1

2}, Dewei Li², Liang Li³, Zhibin Zhao⁴, Liang Li⁴, Tuerganaili Aji⁵, Renyong Lin³, Yingmei Shao⁵, Dominique A Vuitton⁶, Zhigang Tian^{7

8}, Haoyu Sun^{7

8}, Hao Wen¹

Affiliations

¹ State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, Xinjiang Medical University, 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 for Prevention and Case Management of Echinococcosis, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
⁴ Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China.
⁵ Department of Hepatic Hydatid and Hepatobiliary Surgery, Digestive and Vascular Surgery Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
⁶ WHO Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, Department of Parasitology, University Bourgogne Franche-Comté (EA 3181) and University Hospital, Besançon, France.
⁷ Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁸ Institute of Immunology, University of Science and Technology of China, Hefei, China.

^# Contributed equally.

PMID: 34192365
DOI: 10.1002/hep.32035

Involvement of TIGIT in Natural Killer Cell Exhaustion and Immune Escape in Patients and Mouse Model With Liver Echinococcus multilocularis Infection

Chuanshan Zhang et al. Hepatology. 2021 Dec.

. 2021 Dec;74(6):3376-3393.

doi: 10.1002/hep.32035. Epub 2021 Sep 28.

Authors

Affiliations

¹ State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, Xinjiang Medical University, 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 for Prevention and Case Management of Echinococcosis, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
⁴ Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China.
⁵ Department of Hepatic Hydatid and Hepatobiliary Surgery, Digestive and Vascular Surgery Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
⁶ WHO Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, Department of Parasitology, University Bourgogne Franche-Comté (EA 3181) and University Hospital, Besançon, France.
⁷ Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁸ Institute of Immunology, University of Science and Technology of China, Hefei, China.

^# Contributed equally.

PMID: 34192365
DOI: 10.1002/hep.32035

Abstract

Background and aims: Alveolar echinococcosis (AE) is a lethal helminthic liver disease caused by persistent infection with Echinococcus multilocularis. Although more attention has been paid to the immunotolerance of T cells caused by E. multilocularis infection, the role of natural killer (NK) cell, a critical player in liver immunity, is seldom studied.

Approach and results: Here, we observed that NK cells from the blood and closed liver tissue (CLT) of AE patients expressed a higher level of inhibitory receptor TIGIT and were functionally exhausted with a lower expression of granzyme B, perforin, interferon-gamma (IFN-γ), and TNF-α. Addition of anti-TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) monoclonal antibody into AE patients' peripheral blood mononuclear cell culture significantly enhanced the synthesis of IFN-γ and TNF-α by NK cells, indicating the reversion of exhausted NK cells by TIGIT blockade. In the mouse model of E. multilocularis infection, liver and splenic TIGIT⁺ NK cells progressively increased dependent of infection dosage and timing and were less activated and less degranulated with lower cytokine secretion. Furthermore, TIGIT deficiency or blockade in vivo inhibited liver metacestode growth, reduced liver injury, and increased the level of IFN-γ produced by liver NK cells. Interestingly, NK cells from mice with persistent chronic infection expressed a higher level of TIGIT compared to self-healing mice. To look further into the mechanisms, more regulatory CD56^bright and murine CD49a⁺ NK cells with higher TIGIT expression existed in livers of AE patients and mice infected with E. multilocularis, respectively. They coexpressed higher surface programmed death ligand 1 and secreted more IL-10, two strong inducers to mediate the functional exhaustion of NK cells.

Conclusions: Our results indicate that inhibitory receptor TIGIT is involved in NK cell exhaustion and immune escape from E. multilocularis infection.

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References

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1. Gottstein B, Soboslay P, Ortona E, Wang J, Siracusano A, Vuitton D. Immunology of alveolar and cystic echinococcosis (AE and CE). Adv Parasitol 2017;96:1-54.
1. Zhang C, Shao Y, Yang S, Bi X, Li L, Wang H, et al. T-cell tolerance and exhaustion in the clearance of Echinococcus multilocularis: role of inoculum size in a quantitative hepatic experimental model. Sci Rep 2017;7:11153.
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1. Zhang C, Lin R, Li Z, Yang S, Bi X, Wang H, et al. Immune exhaustion of T cells in alveolar echinococcosis patients and its reversal by blocking checkpoint receptor TIGIT in a murine model. Hepatology 2020;71:1297-1315.

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Involvement of TIGIT in Natural Killer Cell Exhaustion and Immune Escape in Patients and Mouse Model With Liver Echinococcus multilocularis Infection

Affiliations

Involvement of TIGIT in Natural Killer Cell Exhaustion and Immune Escape in Patients and Mouse Model With Liver Echinococcus multilocularis Infection

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources