title: 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 CD127(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(+) T cells contributes to the inability of these cell populations to persist and control viral replication.
authors.affiliation: Division of Infection and Immunity and Centre for Sexual Health and HIV Research, University College London, London, United Kingdom.
authors.forename: A Ross
authors.initials: AR
authors.lastname: Lopes
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
authors.forename: Abhishek
authors.initials: A
authors.lastname: Das
authors.forename: Claire
authors.initials: C
authors.lastname: Dunn
authors.forename: Antonia
authors.initials: A
authors.lastname: Kwan
authors.forename: Joanna
authors.initials: J
authors.lastname: Turner
authors.forename: Dimitra
authors.initials: D
authors.lastname: Peppa
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilson
authors.forename: Adam
authors.initials: A
authors.lastname: Gehring
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006509:Hepatitis B / Q000276:immunology / Q000503:physiopathology; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D053699:Interleukin-7 Receptor alpha Subunit; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2