Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load

Abstract

ObjectiveA hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion.DesignBy applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses.ResultsHBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression.ConclusionsOverall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.

Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial

“…Interestingly, it has been published in various pre-clinical studies that an intermediate dose of Ad5based vaccines is typically associated with better quality of T-cells (higher polyfunctionality, strongest proliferative capacity and lower expression of exhaustion markers) compared with higher doses. [26][27][28] Unfortunately, we could not perform additional immune assays such as recently reported in the field (e.g., tetramer analysis, ex vivo ELISPOT, phenotypic analysis 25,[29][30][31] in order to better characterize the detected cells due to limited sample quantities. Such analyses will need to be conducted in future clinical trials.…”

“…In particular, inducing POL-educated T-cells would be important as POL-specific CD8 + T cells appear to be more severely exhausted during CHB than Core ones. 31 POL is a very large antigen, notoriously difficult to purify and engineer in genetically stable vectors for vaccine development. To our knowledge, only one other vaccine beside TG1050, i.e.…”

HBV antiviral immunity: not all CD8 T cells are born equal

“…The two manuscripts, Schuch et al 1 and Hoogeveen et al ,2 in Gut tackle this knowledge gap and undertake a direct and detailed ex vivo analysis of the phenotypic and functional features of CD8 T cells targeting epitopes located in different HBV proteins in patients with acute self-limited hepatitis B and in patients with eAg-negative chronic hepatitis B (CHB).…”

Hepatitis B Core Antigen Impairs the Polarization While Promoting the Production of Inflammatory Cytokines of M2 Macrophages via the TLR2 Pathway

“…HBcAg, acting as an important stimulus in a host of stages of HBV life cycle, possesses the strong immunogenicity. It is said that HBcAg-specific CD8 + T cells of CHB patients may not totally exhausted, therefore can help eliminate HBV infection (29,30). Besides, Cooper et al found the core protein of HBV could upregulate the activation of NF-κB and promote inflammatory cytokine release in THP-1 macrophages in vitro.…”