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

Abstract

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.

Advances in Immunotherapy for Hepatitis B

“…During HBV infection, both the number and fitness of HBV-specific T and B lymphocytes increase significantly [ 47 , 48 , 49 ]. The indispensable role played by HBV-specific CD8 + T cells in the clearance of HBV has been well recognized [ 38 , 48 , 50 , 51 , 52 , 53 ]. Moreover, CD4 + T cells are required to promote the activation and function of these CD8 + T cells.…”

Improving Therapeutic Vaccination against Hepatitis B—Insights from Preclinical Models of Immune Therapy against Persistent Hepatitis B Virus Infection

“…High-level antigen expression has been identified as a key factor in reducing the efficacy of effector T cell responses [88,106] and has been suspected to play a role in attenuating HBV-specific immunity during chronic infection [95,106,107]. Recently, we have demonstrated that reduction of HBV-replication and gene expression through an siRNA or shRNA approach before therapeutic vaccination in two different models of persistent HBV infection in mice increased the efficacy of therapeutic vaccination, to eliminate HBV-expressing hepatocytes and achieve control of persistent infection [59].…”

HBV immune tolerance of HBs-transgenic mice observed through parabiosis with WT mice

“…HBV-specific CD8 + T cells are pivotal in antiviral activity either by indirectly secreting cytokines, such as IFN-γ and TNF-α, or directly killing HBV infected hepatocytes, but their response is weak in chronic hepatitis B (CHB) patients exhibiting immune tolerance ( 7 ). Recently, evidence showed that mMDSCs cross-presenting HBsAg migrated to the thymus and selectively deleted HBsAg-specific CD8 + thymocytes in infants and young patients, resulting in CD8 + T cell tolerance and HBV persistence ( 8 ).…”

“…However, numerous HBV core-specific and HBV polymerase-specific CD8 + T cells with polyfunctionality and long-term memory were detected in chronic HBV-infected patients ( 10 – 12 ). Conversely, HBV-specific CD8 + T cells were demonstrated to be exhausted CD8 + T cells, exhibiting several kinds of inhibitory receptors such as PD-1, CTLA-4, Tim-3, and TIGIT in chronic HBV infection ( 7 , 13 – 15 ). Additionally, HBV antigen-presentation by intrahepatic APCs with weakened costimulatory signals also contributed to peripheral tolerance of HBV-specific CD8 + T cells during chronic HBV infection ( 15 ).…”