Apoptosis associated with ex vivo down-regulation of Bcl-2 and up-regulation of Fas in potential cytotoxic CD8+ T lymphocytes during HIV infection.
In this study, we have investigated whether the enhanced apoptosis of CD4+ and CD8+ T lymphocytes throughout HIV infection was controlled by the bcl-2 proto-oncogene, an inhibitor of programmed cell death (PCD) in mammals. We have analyzed the intracellular expression of the Bcl-2 protein by flow cytometry in freshly isolated peripheral T cells from HIV-infected and noninfected individuals. While no decrease in Bcl-2 expression was detected in the CD4+ T cell subset from the seropositive donors, a reduced level of Bcl-2 was found in a fraction of CD8+ T lymphocytes, with the proportion of these cells increasing as HIV infection progressed. We show that the low Bcl-2-expressing CD8+ T cells were highly susceptible to spontaneous apoptosis upon short term culture. Interestingly, PCD significantly increased when these lymphocytes were cultured in the presence of a Fas-specific mAb, which was related to the high expression of the Fas Ag on their surface. The low Bcl-2 CD8+ subpopulation displayed activation markers CD45RO, HLA-DR, and CD38 and expressed TIA-1-positive, but perforin-negative, granules, while lacking the CD28 Ag. These observations suggest that such low Bcl-2 CD8+ T cells correspond to either immature or end-staged anergic CTLs. Moreover, they indicate that down-regulation of Bcl-2 and up-regulation of Bcl-2 and up-regulation of Fas in CD8+ T lymphocytes, associated with the chronic stimulation of these cells during HIV infection, might render them sensitive to Fas-mediated PCD. Such a Bcl-2/Fas-regulated apoptosis could be responsible for the disappearance of both memory CD45RO+ T cell response and HIV-specific cytotoxic activity occurring in the course of HIV infection and could contribute to AIDS pathogenesis.
Boudet
F
F
Retroviruses and AIDS Department, Pasteur Institute, Paris, France.
Lecoeur
H
H
Gougeon
M L
ML
D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2; D013602:T-Lymphocytes, Cytotoxic / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000502:physiology
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor