Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8(+) T cells.
What governs the increased apoptosis sensitivity of HIV-specific CD8(+) T cells is poorly understood. Here, we examined the involvement of mitochondria in this apoptosis. Remarkably higher mitochondrial mass (MM) was found in HIV-specific compared with CMV-specific CD8(+) T cells from HIV(+) patients and this could not be attributed to their different differentiation status. MM(High) phenotype characterized those CD8(+) T cells from HIV(+) patients that are sensitive to spontaneous and CD95/Fas-induced apoptosis. CD38 expression did not correlate with high MM, whereas Bcl-2 levels were significantly reduced in both CD38(+) and CD38(-) HIV-specific CD8(+) T cells. Although CD38(+) HIV-specific CD8(+) T cells were more susceptible to apoptosis, CD38 expression does not explain on its own the selective apoptosis sensitivity of HIV-specific CD8(+) T cells, as CD38(-) HIV-specific CD8(+) T cells were more apoptotic than CD38(+) CMV-specific ones. Proapoptotic HIV-specific CD8(+) T cells were CD38(+)Bcl-2(Low)MM(High). Copolarization of mitochondria with CD95/Fas capping, very early in CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells, suggests that mitochondria act as an amplification step for this apoptosis. Thus, an extensive mitochondrial network contributes to apoptosis sensitivity of CD8(+) T cells and, when this occurs together with reduced levels of Bcl-2 and chronic activation, determines the proapoptotic state of HIV-specific CD8(+) T cells.
Petrovas
Constantinos
C
Department of Microbiology and Immunology and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, 19129, USA.
Mueller
Yvonne M
YM
Dimitriou
Ioannis D
ID
Altork
Susan R
SR
Banerjee
Anupam
A
Sklar
Peter
P
Mounzer
Karam C
KC
Altman
John D
JD
Katsikis
Peter D
PD
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D006678:HIV / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008933:Mitochondrial Swelling; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012680:Sensitivity and Specificity; D019014:fas Receptor / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D051997:ADP-ribosyl Cyclase 1