Restoration of CD3+CD56+ NKT‐like cell function by TIGIT blockade in inactive carrier and immune tolerant patients of chronic hepatitis B virus infection

• Published in: European journal of immunology 2024-08, Vol.54 (8), p.e2451046-n/a
• Main Authors: Yu, Xiaojing, Zheng, Yuanling, Huang, Ruoyu, Dai, Xiaoran, Kang, Guijie, Wang, Xuefu, Yan, Guoxiu, Ding, Biran, Zheng, Meijuan, Xu, Yuanhong, Zong, Lu
• Format: Article
• Language: English
• Subjects: CD3 antigen; CD3+CD56+ NKT‐like cells; CD56 antigen; Cell culture; CHB; Chronic infection; Cirrhosis; Cytokines; Cytotoxicity; Dendritic cells; Hepatitis; Hepatitis B; Hepatitis B e antigen; Hepatocellular carcinoma; Immune tolerance; Immunological tolerance; Immunotherapy; Liver cancer; TIGIT
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.202451046

Chronic hepatitis B (CHB) virus infection, which can be divided into immune‐tolerant (IT), immune‐active (IA), inactive carrier (IC) phases, and HBeAg‐negative hepatitis (ENEG), can induce liver cirrhosis and eventually hepatocellular carcinoma (HCC). CD3+CD56+ NKT‐like cells play an important role in antiviral immune response. However, the mechanism of NKT‐like cells to mediate immune tolerance remains largely elusive. In this study, we observed circulating NKT‐like cells from IC and IT CHB patients were phenotypically and functionally impaired, manifested by increased expression of inhibitory receptor TIGIT and decreased capacity of secreting antiviral cytokines. Besides, TIGIT+ NKT‐like cells of IC and IT CHB patients expressed lower levels of cytotoxic cytokines than the TIGIT− subset. Furthermore, increased expression of CD155, the ligand of TIGIT, on plasmacytoid dendritic cells (pDCs) was detected in IC and IT CHB patients. Importantly, the co‐culture of NKT‐like cells and pDCs showed that NKT‐like cells restored their antiviral ability after TIGIT blockade upon HBV peptide stimulation in IC and IT CHB patients. In conclusion, our findings suggest that the TIGIT pathway may mediate immune tolerance in IT CHB patients and lead to functional impairment in IC patients, indicating that TIGIT may be a potential therapeutic checkpoint for immunotherapy of CHB patients. NKT‐like cells of the immune carrier (IC) CHB patients who had low HBsAg titers were functionally impaired, while NKT‐like cells of the immune tolerant (IT) CHB patients with high HBsAg titers were immune tolerant. After the TIGIT blockade, the NKT‐like cells of IC and IT patients restored their antiviral function.