Interleukin-7 promotes the survival of human CD4+ effector/memory T cells by up-regulating Bcl-2 proteins and activating the JAK/STAT signalling pathway.
Interleukin-7 (IL-7) is a crucial cytokine involved in T-cell survival and development but its signalling in human T cells, particularly in effector/memory T cells, is poorly documented. In this study, we found that IL-7 protects human CD4(+) effector/memory T cells from apoptosis induced upon the absence of stimulation and cytokines. We show that IL-7 up-regulates not only Bcl-2 but also Bcl-xL and Mcl-1 as well. Interleukin-7-induced activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is sufficient for cell survival and up-regulation of Bcl-2 proteins. In contrast to previous studies with naive T cells, we found that IL-7 is a weak activator of the phosphatidylinositol 3 kinase (PI3K)/AKT (also referred as protein kinase B) pathway and IL-7-mediated cell survival occurs independently from the PI3K/AKT pathway as well as from activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Considering the contribution of both IL-7 and CD4(+) effector/memory T cells to the pathogenesis of autoimmune diseases such as rheumatoid arthritis and colitis, our study suggests that IL-7 can contribute to these diseases by promoting cell survival. A further understanding of the mechanisms of IL-7 signalling in effector/memory T cells associated with autoimmune inflammatory diseases may lead to potential new therapeutic avenues.
Chetoui
Nizar
N
Centre de Recherche en Rhumatologie/Immunologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, and Faculté de Médecine, Université Laval, Québec, PQ, Canada.
Boisvert
Marc
M
Gendron
Steve
S
Aoudjit
Fawzi
F
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002070:Butadienes / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000172:deficiency; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D007376:Interleukin-2 / Q000494:pharmacology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D009025:Morpholines / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; D002070:Butadienes; D061945:Caspase Inhibitors; D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D050791:STAT Transcription Factors; D050799:STAT5 Transcription Factor; C113580:U 0126; D051020:bcl-X Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D017493:Leukocyte Common Antigens; D053148:Caspase 3
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