Costimulation by CD137/4–1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIPshort via phosphatidylinositol 3-kinase and AKT/protein kinase B
✍ Scribed by Lilian Stärck; Christian Scholz; Bernd Dörken; Peter T. Daniel
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 333 KB
- Volume
- 35
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Abstract
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.