The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published 5 August 2002. doi:10.1084/jem.20020307
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© Rockefeller University Press, 0022-1007/2002/8/335/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 3, August 5, 2002 335-348

CD28-dependent Activation of Protein Kinase B/Akt Blocks Fas-mediated Apoptosis by Preventing Death-inducing Signaling Complex Assembly

Russell G. Jones1, Alisha R. Elford1, Michael J. Parsons1, Linda Wu2, Connie M. Krawczyk1, Wen-Chen Yeh1, Razqallah Hakem1, Robert Rottapel1,2, James R. Woodgett1 and Pamela S. Ohashi1,2

1 Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada
2 Department of Immunology, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada

Address correspondence to Pamela S. Ohashi, Ontario Cancer Institute, 610 University Ave., 8-327 Toronto, Ontario M5G 2M9, Canada. Phone: 416-946-2000, ext. 5471; Fax: 416-946-2086; E-mail: pohashi{at}uhnres.utoronto.ca

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 (PKB{alpha}/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 PKB{alpha}. 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 (PIP3) and influences PKB{alpha} 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.

Key Words: CD28 • PKB/Akt • apoptosis • Fas • caspase-8


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