Apoptosis by IL-2 deprivation in human CD8+ T cell blasts predominates over death receptor ligation, requires Bim expression and is associated with Mcl-1 loss.
The mechanisms responsible for the down-modulation of the activation of separated CD4(+) or CD8(+) human T cell blasts were studied using cells obtained from healthy donors. In the absence of IL-2, human CD4(+) T cell blasts were sensitive to both FasL and Apo2L/TRAIL, but human CD8(+) T cell blasts died, with no additional effect of death receptor ligation. CD8(+) T cell blasts were more sensitive than CD4(+) T cell blasts to apoptosis induction by IL-2 deprivation, which was associated with a decrease in the expression of anti-apoptotic proteins of the Bcl-2 family, especially of Mcl-1 in CD8(+) T cell blasts. The maintenance of high levels of Bim expression was also necessary, since down-modulation of Bim expression by siRNA in normal human CD8(+) T cell blasts greatly reduced apoptosis by IL-2 deprivation. These data, together with previous works, point to an important role of the presence or absence of immuno-stimulatory cytokines in the type of regulation of human CD8(+) T cell responses (death by cytokine deprivation versus death receptor inhibition of cytokine-dependent growth).
Bosque
Alberto
A
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza E-50009, Spain.
Marzo
Isabel
I
Naval
Javier
J
Anel
Alberto
A
D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000172:deficiency* / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000276:immunology / Q000378:metabolism; D053218:Receptors, Death Domain / Q000276:immunology / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D007376:Interleukin-2; D008024:Ligands; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain