Anita Schuch1,2,3, Elahe Salimi Alizei1,4,3, Kathrin Heim1,2,3, Dominik Wieland1,3, Muthamia M. Kiraithe1,3, Janine Kemming1,2,3, Sian Llewellyn‐Lacey5, Özlem Soğukpınar1,3, Yi Ni6, Stephan Urban6,7, Peter Jan Zimmermann1,2,3, Michael Nassal1,3, Florian Emmerich8, David A. Price5, Bertram Bengsch1,3, Hendrik Luxenburger1,3, Christoph Neumann‐Haefelin1,3, Maike Hofmann1,3, Robert Thimme9
1Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
2Faculty of Biology, University of Freiburg, Freiburg, Germany
3Faculty of Medicine, University of Freiburg, Freiburg, Germany
4Faculty of Chemistry and Pharmacy, University of Freiburg, Freiburg, Germany
5Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
6Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany
7German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
8Institute for Cell and Gene Therapy, University Hospital Freiburg, Freiburg, Germany
9Department of Internal Medicine II, University Hospital Freiburg, Freiburg 79106, Germany
Tóm tắt
ObjectiveA 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.DesignBy 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.ResultsHBV-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.ConclusionsOverall, 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.
