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FRI-138
HBVcore- versus HBVpolymerase-specific CD8+ T cells differ in
chronically HBV-infected patients
Kathrin Heim1,2, Anita Schuch1,2, Elahe Salimi Alizei1,3,
Janine Kemming1,2, Hendrik Luxenburger1,
Christoph Neumann-Haefelin1, Maike Hofmann1, Robert Thimme1.
1Department of Medicine II, University Hospital Freiburg, Freiburg,
Germany; 2Faculty of Biology, University of Freiburg, Freiburg, Germany;
3Faculty of Chemistry and Pharmacy, University of Freiburg, Freiburg,
Germany
Email: [email protected]
Background and aims: Chronic Hepatitis B virus (HBV) infection is
characterized by the presence of impaired HBV-specific CD8+ T-cell
responses. T-cell exhaustion induced by persistent antigen stimulation
is considered a major mechanismunderlying HBV-specific CD8+
T-cell failure. However, due to low frequencies of detectable HBVspecific
CD8+ T-cell populations in chronically HBV-infected patients,
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.
Method: To enhance detection of HBV-specific CD8+ T-cell responses,
we performed pMHCI tetramer-based enrichment of circulating
CD8+ T cells specific for HBV core- and polymerase-derived epitopes
in 88 cHBV patients with low viral loads. Subsequently, phenotypic
and functional in-depth analyses were performed using 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+, showed lowTOX expression and lacked signs
of terminal exhaustion, possibly reflecting weak ongoing cognateantigen recognition. However, within the HBV-specific population,
we found significant differences in phenotype and function between
core- and polymerase-specific CD8+ T cells. Indeed, more corespecific
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. These differences
were only detectable in HBV-specific CD8+ T cells obtained
from chronically infected patients and not from patients who
resolved HBV.
Conclusion: 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. |
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发表于 2019-4-8 15:00