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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. 1Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
  2. 2Faculty of Medicine, University of Freiburg, Freiburg, Germany
  3. 3Faculty of Biology, University of Freiburg, Freiburg, Germany
  4. 4Faculty of Chemistry and Pharmacy, University of Freiburg, Freiburg, Germany
  5. 5Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
  6. 6Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany
  7. 7German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
  8. 8Institute 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}uniklinik-freiburg.de

Abstract

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

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • 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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