title: CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly.
abstract: The T cell costimulatory molecule CD28 is important for T cell survival, yet both the signaling pathways downstream of CD28 and the apoptotic pathways they antagonize remain poorly understood. Here we demonstrate that CD4(+) T cells from CD28-deficient mice show increased susceptibility to Fas-mediated apoptosis via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. Protein kinase B (PKBalpha/Akt1) is an important serine/threonine kinase that promotes survival downstream of PI3K signals. To understand how PI3K-mediated signals downstream of CD28 contribute to T cell survival, we examined Fas-mediated apoptosis in T cells expressing an active form of PKBalpha. Our data demonstrate that T cells expressing active PKB are resistant to Fas-mediated apoptosis in vivo and in vitro. PKB transgenic T cells show reduced activation of caspase-8, BID, and caspase-3 due to impaired recruitment of procaspase-8 to the death-inducing signaling complex (DISC). Similar alterations are seen in T cells from mice which are haploinsufficient for PTEN, a lipid phosphatase that regulates phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) and influences PKBalpha activity. These findings provide a novel link between CD28 and an important apoptosis pathway in vivo, and demonstrate that PI3K/PKB signaling prevents apoptosis by inhibiting DISC assembly.
authors.affiliation: Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Canada.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parsons
authors.forename: Linda
authors.initials: L
authors.lastname: Wu
authors.forename: Connie M
authors.initials: CM
authors.lastname: Krawczyk
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity; D018106:CD28 Antigens / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
chemical_list: D018106:CD28 Antigens; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse