Enforced cytotoxic signature of HBV pol455-specific CD8 T cells in chronic HBV infection

T-cell exhaustion represents a distinct T-cell differentiation program associated with chronic viral infections. Several studies have shown that exhausted CD8+ T cells are heterogeneous. In chronic HBV infection, we and others observed major differences in phenotype and function as well as the degree of dysfunction of HBV-specific CD8+ T cells targeting different antigens. The aim of this study was to investigate the molecular heterogeneity of these differences in antigen-specific HBV-specific CD8+ T-cell immunity.

We conducted single-cell RNA sequencing of HBV-specific CD8+ T cells targeting different antigens, HBVcore18 and HBVpol455, obtained from chronically HBV-infected patients. Cluster analysis of single-cell transcriptomes revealed a different subset diversification of HBVcore18- versus HBVpol455-specific CD8+ T cells. In particular, HBVcore18-specific CD8+ T cells were mostly comprised of precursor-like/memory-like exhausted T-cell subsets. Within HBVpol455-specific CD8+ T cells, we could identify a cluster of cells that highly expressed cytotoxic genes including GNLY, GRMB, NKG7, PRF1. The differential transcriptional profile of HBVpol455-specific CD8+ T cells was further confirmed ex vivo after pMHCI tetramer-based enrichment. Indeed, at the protein level, we also detected a higher cytotoxic potential of HBVpol455-specific CD8 T cells obtained from patients who endogenously control the viral infection in comparison to patients requiring antiviral therapy.

In sum, our data show different molecular and functional characteristics of virus-specific CD8+ T-cell responses targeting different HBV antigens linked to control of infection. This may have potential implications for the design of immunotherapeutic approaches in HBV cure.

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Artikel online veröffentlicht:
26. Januar 2022