A dual role of IFN-alpha in the balance between proliferation and death of human CD4+ T lymphocytes during primary response.
Type I IFNs (IFN-alphabeta) enhance immune responses, notably T cell-mediated responses, in part by promoting the functional activities of dendritic cells. In this study, we analyzed the direct impact of IFN-alpha on proliferative and apoptotic signals upon in vitro activation of human naive CD4+ T lymphocytes. We demonstrate that IFN-alpha protects T cells from the intrinsic mitochondrial-dependent apoptosis early upon TCR/CD28 activation. IFN-alpha acts by delaying entry of cells into the G1 phase of the cell cycle, as well as by increasing Bcl-2 and limiting Bax activation. Later, upon activation, T cells that were exposed to IFN-alpha showed increased levels of surface Fas associated with partially processed caspase-8, a key component of the extrinsic apoptotic pathway. Caspase-8 processing was augmented furthermore by Fas ligation. Overall, these findings support a model whereby IFN-alpha favors an enhanced clonal expansion, yet it sensitizes cells to the Ag-induced cell death occurring at the end of an immune response. These observations point to a complex role of type I IFN in regulating the magnitude of proliferation and survival of naive CD4+ T cells during primary response and underline how crucial could be the timing of exposure to this cytokine.
Dondi
Elisabetta
E
Unité de Signalisation des Cytokines, Institut Pasteur, Paris, France.
Roué
Gaël
G
Yuste
Victor J
VJ
Susin
Santos A
SA
Pellegrini
Sandra
S
D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D016898:Interferon-alpha; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases