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

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 CD56bright 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.

Primary Infection by E. multilocularis Induces Distinct Patterns of Cross Talk between Hepatic Natural Killer T Cells and Regulatory T Cells in Mice

“…The finding that NKT cells expand in patients with AE (32) supports the finding of the present study. Given the fact that many microbes and parasites are enriched in lipid antigens and NKT cells are a T cell subset that can recognize lipid antigens, it is reasonable to speculate about the potential relevance of NKT cells to control the early development of infection and control of the disease at later stages.…”

“…4). This may be paralleled with the TNF production seen in NK cells (32). While clinical evidence of the opportunistic properties of AE is growing (6), the relevance of TNF signaling has been suggested once (43).…”

Natural Killer Cells in Hepatic Ischemia-Reperfusion Injury

“…NK cell signaling in hepatic I/R is primarily mediated by engagement of their activating receptors (mainly including CD16, NKG2C:CD94, NKG2D, NKp46, NKp44, NKp30, CD226, and natural killer granule 7) and inhibitory receptors (largely composed of CD96, TIGIT, LAG3, killer cell immunoglobulin receptor (KIR) (Ly49 receptor in mice), and NKG2A:CD94), and the dynamic balance between them determines the responsiveness of NK cells ( 29 , 30 ). Notably, the human KIR (Ly49 molecule in mice) and NKG2A:CD94 could recognize MHC class I molecules that are abundantly expressed on normal cells, thereby inhibiting NK cell function to ensure perfect tolerance to their own healthy cells ( 29 , 31 ).…”

Advances in the pharmacological treatment of hepatic alveolar echinococcosis: From laboratory to clinic

“…The lack or blocking of TIGIT partially inhibits the growth of E. multilocular by reversing the damaged function of NK cells. The results suggest that targeting TIGIT may be a potential immunotherapeutic strategy for the treatment of patients with AE ( Zhang et al, 2021 ; Table 1 ).…”