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Original article
Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load
  1. Anita Schuch1,2,3,
  2. Elahe Salimi Alizei1,2,4,
  3. Kathrin Heim1,2,3,
  4. Dominik Wieland1,2,
  5. Michael Muthamia Kiraithe1,2,
  6. Janine Kemming1,2,3,
  7. Sian Llewellyn-Lacey5,
  8. Özlem Sogukpinar1,2,
  9. Yi Ni6,
  10. Stephan Urban6,7,
  11. Peter Zimmermann1,2,3,
  12. Michael Nassal1,2,
  13. Florian Emmerich8,
  14. David A Price5,
  15. Bertram Bengsch1,2,
  16. Hendrik Luxenburger1,2,
  17. Christoph Neumann-Haefelin1,2,
  18. Maike Hofmann1,2,
  19. Robert Thimme1,2
  1. 1 Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
  2. 2 Faculty of Medicine, University of Freiburg, Freiburg, Germany
  3. 3 Faculty of Biology, University of Freiburg, Freiburg, Germany
  4. 4 Faculty of Chemistry and Pharmacy, University of Freiburg, Freiburg, Germany
  5. 5 Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
  6. 6 Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany
  7. 7 German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
  8. 8 Institute for Cell and Gene Therapy, University Hospital Freiburg, Freiburg, Germany
  1. Correspondence to Professor Robert Thimme, Department of Internal Medicine II, University Hospital Freiburg, Freiburg 79106, Germany; robert.thimme{at}


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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