Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection
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
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
View: Text | PDF
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

×

Figure 2

Bim expression is increased at the protein level in HBV-specific CD8+ T cells from patients with CHB.

Options: View larger image (or click on image) Download as PowerPoint
Bim expression is increased at the protein level in HBV-specific CD8+ T ...
(A) Representative example of Bim expression in HBV-specific CD8+ T cells from resolved and CHB patients (left and middle) and the cumulative data (right). Bim expression in resolved responses was similar to background levels with an isotype control. (B) Representative example of Bim expression in total CD8+ T cells (T) and HBV-specific CD8+ T cells (H) in a patient with CHB (left and middle) and cumulative data (right). (C) Correlation between viral load and Bim expression in HBV-specific CD8+ T responses in CHB patients (left) and relative levels of Bim expression in resolved (R) and CHB patients segregated according to eAg status (right). (D) Representative example of Bim expression directly ex vivo in HBV-specific CD8+ T cells in resolved and CHB individuals (left and middle) and cumulative data (right). (E) Bim expression directly ex vivo in tetramer-positive HBV-specific CD8+ T cell responses from resolved and CHB patients. Shown are examples of tetramer and Bim staining (left and middle) and summary data for all responses (right). Significance testing of all cumulative data by Mann-Whitney test. (F) Bim expression directly ex vivo in HBV-specific CD8+ T cells quantified over the course of acute HBV infection (using overlapping peptides in HLA-A2– patient R17 and using HLA-A2/HBV tetramers in 2 HLA-A2+ patients, R7 and R13). Bim levels in HBV-specific CD8+ T cells are plotted against HBV DNA, with serology and ALT in the acute and resolved (right of dotted line) phases indicated below. Error bars indicate mean ± SD.