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
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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 1

cDNA microarray data of HBV-specific CD8+ T cells from resolved and CHB patients.

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cDNA microarray data of HBV-specific CD8+ T cells from resolved and CHB ...
(A) Envelope-specific CD8+ T cells were purified by flow cytometric sorting of a short-term PBMC line from a chronic patient (middle and left plots, respectively). mRNA extracted from the purified cells was then profiled by dual-color cDNA microarray technology (right). (B) TreeView analysis of average linkage hierarchically clustered (with self-organized mapping) gene expression data. The top dendrogram represents the similarity between individual arrayed samples (vertical plane) based on the global gene expression profile; a yellow line segregates the main clusters: chronic (C) and resolved (R). The blue box highlights a section of the heat map where a group of genes exhibited marked upregulation in branch C compared with R (listed with original and current unigene references on the right; genes in red participate in apoptosis; genes overlapping with the SAM short list are indicated by asterisks). (C) SAM plot illustrating the most significant differentially regulated genes (false discovery rate, 1.3%) between the group with chronic and that with resolved HBV infection. (D) cDNA array data of 5 highly significant apoptosis-related genes. Error bars indicate mean ± SD.