Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIP(short) via phosphatidylinositol 3-kinase and AKT/protein kinase B.
Costimulation is essential for induction of T lymphocyte proliferation and inhibition of activation-induced cell death. While signaling pathways activated following the ligation of the costimulatory molecule CD28 are well defined, less is known about the molecular events induced by alternative costimulators. CD137/4-1BB, a costimulatory member of the tumor necrosis factor receptor family, plays an important role during late primary T cell stimulation. Here, we demonstrate for the first time that inhibition of activation-induced cell death by exposure to the CD137/4-1BB ligand involves up-regulation of the anti-apoptotic protein c-FLIP(short). Inhibition of T cell death by 4-1BB ligation and up-regulation of c-FLIP(short) and Bcl-x(L) were abolished by blocking the phosphatidylinositol 3-kinase or the AKT/protein kinase B, which also mediate CD28-induced inhibition of activation-induced cell death. Our findings, therefore, demonstrate that costimulatory molecules, although belonging to different protein families and participating in distinct upstream signaling pathways, employ common downstream signaling pathways.
Stärck
Lilian
L
Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Berlin, Germany.
Scholz
Christian
C
Dörken
Bernd
B
Daniel
Peter T
PT
D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002455:Cell Division / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D051020:bcl-X Protein
D015703:Antigens, CD; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C506386:CFLAR protein, human; C506387:Cflar protein, mouse; C505714:TNFRSF9 protein, human; C505715:Tnfrsf9 protein, mouse; C494918:AKT1 protein, human