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Original article
Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection
  1. Ruben C Hoogeveen1,2,
  2. Maxwell P Robidoux1,
  3. Tatjana Schwarz3,
  4. Laura Heydmann4,
  5. James A Cheney1,
  6. Daniel Kvistad1,
  7. Jasneet Aneja1,
  8. Juliana G Melgaço5,
  9. Carlos A Fernandes6,
  10. Raymond T Chung1,
  11. Andre Boonstra2,
  12. Arthur Y Kim7,
  13. Thomas F Baumert4,
  14. Jörg Timm3,
  15. Lia L Lewis-Ximenez5,
  16. Pierre Tonnerre1,
  17. Georg M Lauer1
  1. 1 Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  2. 2 Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
  3. 3 Institute of Virology, Heinrich Heine University, University Hospital, Düsseldorf, Germany
  4. 4 Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, Strasbourg, France
  5. 5 Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
  6. 6 Laboratório Central de Saúde Pública Noel Nutels, Rio de Janeiro, Brazil
  7. 7 Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Georg M Lauer, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston MA 02114, USA; glauer{at}mgh.harvard.edu

Abstract

Objective Chronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control.

Design The phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection.

Results We detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities.

Conclusion HBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure.

  • hepatitis B
  • acute hepatitis
  • chronic hepatitis
  • cellular immunity

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Footnotes

  • PT and GML have a shared last authorship.

  • PT and GML contributed equally.

  • Contributors RCH designed and performed the experiments, analysed the data and wrote the paper. MPR and TS performed the experiments and analysed the data. JAC, DK and LH performed the experiments. JA, JGM, CAF, RCH, AB, AYK and LLLX contributed to design and recruitment of clinical cohorts and to data interpretation. JT and TFB analysed the data and advised on data interpretation. PT conceived, designed and performed the experiments, analysed the data and advised on data interpretation. GML conceived and supervised the study, analysed the data, provided funding and wrote the paper.

  • Funding This work was supported in parts by NIH U01 AI131314 (to GML, AYK and LLLX) and U19 AI082630 (to GML, RTC and AYK). RCH received a Ter Meulen Fonds Fellowship by the Dutch Royal Academy of Arts and Sciences.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval Partners Human Research Committee; the Institutional Ethical Review Board of the Erasmus Medical Center; the Ethics Board of the Oswaldo Cruz Institute.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional unpublished data available.

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