Objective A 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.
Design By 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.
Results HBV-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.
Conclusions Overall, 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.
- T lymphocytes
- BCL-2 family proteins
- hepatitis B
- chronic viral hepatitis
- immune response
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ESA and KH contributed equally.
MH and RT contributed equally.
Contributors AS designed, performed and analysed experiments and wrote the manuscript; ESA, KH, DW, MMK, JK and OS performed experiments; YN and PZ participated in developing experimental procedures; SL-L, SU, MN and DAP provided reagents; BB, CN-H and HL contributed to data interpretation; FE conducted HLA genotyping; MH and RT designed the study, contributed to experimental planning, interpreted data and wrote the manuscript.
Funding This work was supported by the SFB 1160/IMPATH (Project 08) of the German Research Foundation (DFG) to RT, by the SFB 1160/IMPATH (Project 10) of the DFG to CN-H, by the SFB/TRR179 (TP16) of the DFG to MN and by the SFB/TRR179 (TP15) of the DFG to SU. MH was supported by a DZIF maternity leave stipend (TI 07.005_Hofmann) and by the SFB/TRR179 (TP01) of the DFG.
Competing interests None declared.
Patient consent Not required.
Ethics approval The study was conducted according to federal guidelines, local ethics committee regulations (Albert-Ludwigs-University, Freiburg, Germany, HBUF 474/14 and 299/01) and the Declaration of Helsinki (1975).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data are published in the manuscript.
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