HBV-Specific CD8+ T-Cell Tolerance in the Liver

• Published in: Frontiers in immunology Vol. 12; p. 721975
• Main Authors: Baudi, Ian, Kawashima, Keigo, Isogawa, Masanori
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 06.08.2021
• Subjects: Animals; Antigens - immunology; Biomarkers; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; co-inhibitory signaling; Cytotoxicity, Immunologic; Energy Metabolism; Epitopes, T-Lymphocyte - immunology; Hepatitis B - immunology; Hepatitis B - metabolism; Hepatitis B - pathology; Hepatitis B - virology; Hepatitis B virus - immunology; Host-Pathogen Interactions - immunology; Humans; Immune Tolerance; Immunology; Immunomodulation; interferon signaling; intrahepatic antigen recognition; Liver - immunology; Liver - metabolism; Liver - pathology; Liver - virology; liver tolerance; Lymphocyte Activation - immunology; metabolic regulation; T cell exhaustion; interferon signaling; intrahepatic antigen recognition; hepatitis B virus; T cell exhaustion; co-inhibitory signaling; liver tolerance; metabolic regulation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.721975

Hepatitis B virus (HBV) remains a leading cause of liver-related morbidity and mortality through chronic hepatitis that may progress to liver cirrhosis and cancer. The central role played by HBV-specific CD8+ T cells in the clearance of acute HBV infection, and HBV-related liver injury is now well established. Vigorous, multifunctional CD8+ T cell responses are usually induced in most adult-onset HBV infections, while chronic hepatitis B (CHB) is characterized by quantitatively and qualitatively weak HBV-specific CD8+ T cell responses. The molecular basis of this dichotomy is poorly understood. Genomic analysis of dysfunctional HBV-specific CD8+ T cells in CHB patients and various mouse models suggest that multifaceted mechanisms including negative signaling and metabolic abnormalities cooperatively establish CD8+ T cell dysfunction. Immunoregulatory cell populations in the liver, including liver resident dendritic cells (DCs), hepatic stellate cells (HSCs), myeloid-derived suppressor cells (MDSCs), may contribute to intrahepatic CD8+ T cell dysfunction through the production of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines and the expression of co-inhibitory molecules. A series of recent studies with mouse models of HBV infection suggest that genetic and epigenetic changes in dysfunctional CD8+ T cells are the manifestation of prolonged antigenic stimulation, as well as the absence of co-stimulatory or cytokine signaling. These new findings may provide potential new targets for immunotherapy aiming at invigorating HBV-specific CD8+ T cells, which hopefully cures CHB.