Original Article

Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor B Activation, and Bcl-X_L Levels In Vivo

Correspondence to: Pamela S. Ohashi, Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, 610 University Ave., Toronto, Ontario M5G 2M9, Canada. Tel:416-946-4501, ext. 5470 Fax:416-946-2086 E-mail: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-X_L. In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-B activation via accelerated degradation of the NF-B inhibitory protein IB. 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-X_L, and NF-B) in vivo in T lymphocytes.

Key Words: PKB/Akt, Bcl-X_L, apoptosis, thymocyte selection, NF-B

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