Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection
A. Ross Lopes, … , Antonio Bertoletti, Mala K. Maini
A. Ross Lopes, … , Antonio Bertoletti, Mala K. Maini
Published April 8, 2008
Citation Information: J Clin Invest. 2008;118(5):1835-1845. https://doi.org/10.1172/JCI33402.
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Research Article Virology

Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection

Abstract

HBV-specific CD8+ T cells are critical for a successful immune response to HBV infection. They are markedly diminished in number in patients who fail to control the virus, but the mechanisms resulting in their depletion remain ill defined. Here, we dissected the defective HBV-specific CD8+ T cell response associated with chronic HBV infection by gene expression profiling. We found that HBV-specific CD8+ T cells from patients with different clinical outcomes could be distinguished by their patterns of gene expression. Microarray analysis revealed that overlapping clusters of functionally related apoptotic genes were upregulated in HBV-specific CD8+ T cells from patients with chronic compared with resolved infection. Further analysis confirmed that levels of the proapoptotic protein Bcl2-interacting mediator (Bim) were upregulated in HBV-specific CD8+ T cells from patients with chronic HBV infection. Blocking Bim-mediated apoptosis enhanced recovery of HBV-specific CD8+ T cells both in culture and directly ex vivo. Consistent with evidence that Bim mediates apoptosis of CD8+ T cells expressing low levels of CD127 (IL-7R), the few surviving HBV-specific CD8+ T cells were CD127hi and had elevated levels of the antiapoptotic protein Mcl1, suggesting they were amenable to IL-7–mediated rescue from apoptosis. We therefore postulate that Bim-mediated attrition of HBV-specific CD8+ T cells contributes to the inability of these cell populations to persist and control viral replication.

Authors

A. Ross Lopes, Paul Kellam, Abhishek Das, Claire Dunn, Antonia Kwan, Joanna Turner, Dimitra Peppa, Richard J. Gilson, Adam Gehring, Antonio Bertoletti, Mala K. Maini

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Figure 3

Rescue of in vitro–cultured HBV-specific CD8+ T cells derived from individuals with CHB.

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Rescue of in vitro–cultured HBV-specific CD8+ T cells derived from indiv...
Representative flow cytometry plots and cumulative data (below) showing the effect of pancaspase inhibition on the detection of envelope and core-specific CD8+ T cells (A and B, respectively) in 10-day peptide-stimulated cultures of PBMCs from individuals with chronic infection. Differences in responses with and without caspase inhibition were calculated with the paired Student’s t test (P < 0.0001). (C) Representative plots of the detection of HBV-specific CD8+ T cells in short-term lines of PBMCs from an individual with chronic infection utilizing pools of overlapping peptides corresponding to the HBV precore/core (PreC/C), X, envelope (Ep1 and Ep2), and polymerase (Pp1–4) proteins with and without caspase inhibition. (D) Influenza A–specific CD8+ T cells detected in short-term lines from individuals with chronic infection ± caspase inhibition. (E) HBV-specific CD8+ T responses detected in short-term lines from resolved individuals with and without caspase inhibition. (F) HBV-specific CD8+ T cell rescue following specific inhibition of proapoptotic Bax in short-term lines from patients with chronic infection.