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Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
Faculty of Medicine, University of Freiburg, Freiburg, Germany
Faculty of Biology, University of Freiburg, Freiburg, Germany
Faculty of Chemistry and Pharmacy, University of Freiburg, Freiburg, Germany
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany
German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
Institute for Cell and Gene Therapy, University Hospital Freiburg, Freiburg, Germany
Correspondence to Professor Robert Thimme, Department of Internal Medicine II, University Hospital Freiburg, Freiburg 79106, Germany; [email protected]
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.
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/.
http://dx.doi.org/10.1136/gutjnl-2018-316641
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Significance of this study
What is already known on this subject?
HBV-specific CD8+ T cells play a central role in the elimination of HBV infection.
Frequencies of HBV-specific CD8+ T cells in chronic HBV infection are very low reflected by low detection rates applying ex vivo peptide-loaded MHC I (pMHC I) tetramer staining.
Detectable HBV-specific CD8+ T cells are functionally impaired, exhibit mitochondrial alterations, express inhibitory receptors and display dysregulation of T-bet.
What are the new findings?
By applying a pMHC I tetramer-based enrichment strategy, we could detect HBV-specific CD8+ T cells in the majority of chronically HBV-infected patients.
Env183-specific CD8+ T cells are hardly detectable by pMHC I tetramer-based enrichment in chronically HBV-infected patients.
HBV-specific CD8+ T cells targeting core18/141and pol455/173 epitopes are not terminally exhausted but predominantly exhibit a memory-like phenotype in chronic infection.
Core18/141 and pol455/173-specific CD8+ T cells differ in frequency, phenotype and function in chronic HBV infection but not in resolved HBV infection.
Dysregulated TCF1/BCL2 expression limits the expansion capacity of pol455/173-specific CD8+ T cells in chronic HBV infection.
How might it impact on clinical practice in the foreseeable future?
These findings have potential implications for the design of T cell-targeted therapeutic approaches in HBV cure. |
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发表于 2019-4-9 16:30