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

HBV-specific [CD8.sup.+] 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.su...

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Bibliographic Details
Published in:The Journal of clinical investigation 2008-05, Vol.118 (5), p.1835
Main Authors: Lopes, A. Ross, Kellam, Paul, Das, Abhishek, Dunn, Claire, Kwan, Antonia, Turner, Joanna, Peppa, Dimitra, Gilson, Richard J, Gehring, Adam, Bertoletti, Antonio, Maini, Mala K
Format: Article
Language:English
Subjects:
Care and treatment
Diagnosis
Health aspects
Hepatitis
Immunotherapy
T cells
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Summary:HBV-specific [CD8.sup.+] 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.sup.+] T cell response associated with chronic HBV infection by gene expression profiling. We found that HBV-specific [CD8.sup.+] 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.sup.+] 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.sup.+] T cells from patients with chronic HBV infection. Blocking Bim-mediated apoptosis enhanced recovery of HBV-specific [CD8.sup.+] T cells both in culture and directly ex vivo. Consistent with evidence that Bim mediates apoptosis of [CD8.sup.+] T cells expressing low levels of CD127 (IL-7R), the few surviving HBV-specific [CD8.sup.+] T cells were [CD127.sup.hi] 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.sup.+] T cells contributes to the inability of these cell populations to persist and control viral replication.
ISSN:0021-9738