Z Gastroenterol 2019; 57(01): e7
DOI: 10.1055/s-0038-1677258
Lectures Session 5. Viral Hepatitis, Immunology
Georg Thieme Verlag KG Stuttgart · New York

Phenotypic and functional differences of HBVcore- versus HBVpolymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load

K Heim
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
2   Faculty of Biology, University of Freiburg, Schänzlestraße 1, Freiburg 79104, Germany
,
A Schuch
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
2   Faculty of Biology, University of Freiburg, Schänzlestraße 1, Freiburg 79104, Germany
,
E Salimi Alizei
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
3   Faculty of Chemistry and Pharmacy, University of Freiburg, Hebelstraße 27, Freiburg 79104, Germany
,
J Kemming
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
2   Faculty of Biology, University of Freiburg, Schänzlestraße 1, Freiburg 79104, Germany
,
Y Ni
4   Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Im Neuenheimer Feld 672, Heidelberg 69120, Germany
,
S Urban
4   Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Im Neuenheimer Feld 672, Heidelberg 69120, Germany
5   German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg 69120, Germany
,
P Zimmermann
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
2   Faculty of Biology, University of Freiburg, Schänzlestraße 1, Freiburg 79104, Germany
,
M Nassal
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
,
B Bengsch
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
,
H Luxenburger
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
,
C Neumann-Haefelin
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
,
M Hofmann
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
,
R Thimme
1   Department of Medicine II, University Hospital Freiburg – Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

Also available at
 

Background and Aims:

Chronic Hepatitis B virus (cHBV) infection results in impaired HBV-specific CD8+ T-cell responses, a phenomenon called T-cell exhaustion. 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.

Methods:

In this study, an enrichment based on peptide-loaded MHCI-tetramers was applied to increase the detection sensitivity of circulating HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins. Subsequently, phenotypic and functional in-depth analyses were performed in 88 chronically HBV-infected patients with low viral load by using high-dimensional multicolor flow cytometry. Patients were pre-selected for autologous viral sequences that matched the targeted epitopes by the analyzed HBV-specific CD8+ T cells.

Results:

We were able to detect HBV-specific CD8+ T cells ex vivo in the majority (> 80%) of tested patients. Specifically, core- and polymerase-, but not envelope-specific CD8+ T cells were frequently found. Interestingly, these HBV-specific CD8+ T cells exhibited a predominantly less differentiated memory-like phenotype characterized by CD127+PD1+ and lacked signs of terminal exhaustion, possibly reflecting weak ongoing cognate antigen recognition in the analyzed low viral load patients. However, within the HBV-specific population, we found significant differences in phenotype and function between core- and polymerase-specific CD8+ T cells. Indeed, more core-specific CD8+ T cells displayed the CD127+PD1+ memory-like phenotype compared to polymerase-specific CD8+ T cells. This observation is in line with the advanced differentiation of polymerase-specific CD8+ T cells towards more severe T-cell exhaustion marked by higher CD38, KLRG1 and Eomes expression accompanied by low T-bet levels and down-regulation of CD127. Polymerase-specific CD8+ T cells also exhibited a reduced expansion capacity compared to core-specific CD8+ T cells that was linked to dysregulated TCF1/BCL2 and high Eomes expression in polymerase-specific CD8+ T cells.

Conclusions:

Overall, the results of our study show different molecular mechanisms underlying impaired T-cell responses with respect to the targeted HBV antigens core versus polymerase in cHBV infection. This may have potential implications for the design of immunotherapeutic approaches in HBV cure.