The Journal of Experimental Medicine
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Published online 15 May 2000.
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© The Rockefeller University Press, 0022-1007/2000/5/1721/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 10, May 15, 2000 1721-1734

Original Article

Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor {kappa}b Activation, and Bcl-XL Levels in Vivo

Russell G. Jonesa, Michael Parsonsa, Madeleine Bonnardc, Vera S.F. Chana, Wen-Chen Yeha,c, James R. Woodgetta, and Pamela S. Ohashia,b

a Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada
b Department of Immunology, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada
c Amgen Institute, Toronto, Ontario M5G 2C1, Canada
Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, 610 University Ave., Toronto, Ontario M5G 2M9, Canada.416-946-2086416-946-4501, ext. 5470

pohashi{at}oci.utoronto.ca

The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4+CD8+ double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I–restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen–specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-XL. In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-{kappa}B activation via accelerated degradation of the NF-{kappa}B inhibitory protein I{kappa}B{alpha}. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-XL, and NF-{kappa}B) in vivo in T lymphocytes.

Key Words: PKB/Akt • Bcl-XL • apoptosis • thymocyte selection • NF-{kappa}B

Abbreviations used in this paper: 7AAD, 7-amino-actinomycin D; DISC, death-inducing signaling complex; DP, double positive; FTOC, fetal thymic organ culture; HSA, heat-stable antigen; LCMV, lymphocytic choriomeningitis virus; NF, nuclear factor; PI, propidium iodide; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; RT, reverse transcription; SP, single positive.

R.G. Jones and M. Parsons contributed equally to this work.

© 2000 The Rockefeller University Press


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