Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 35, Issue 4, Pages 1257-1266Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.200425686
Keywords
4-IBB; T cell; c-FLIPshort; PI3 kinase
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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-FLIPshort. Inhibition of T cell death by 4-1BB ligation and up-regulation of c-FLIPshort 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.
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