INTERMEDIATE AFFINITY INTERLEUKIN-2 RECEPTOR MEDIATES SURVIVAL VIA A PHOSPHATIDYLINOSITOL 3-KINASE-DEPENDENT PATHWAY

Peripheral blood T lymphocytes require two signals to enter and progre ss along the cell cycle from their natural quiescent state, The first activation signal is provided by the stimulation through the T cell re ceptor, which induces the synthesis of cyclins and the expression of t he high affinity interleukin-2 receptor. The second signal, required t o enter the S phase, is generated upon binding of interleukin-2 to the high affinity alpha beta gamma interleukin-2 receptor. However, resti ng T cells already express intermediate affinity beta gamma interleuki n-2 receptors, As shown here, T cell stimulation through intermediate affinity receptors is capable of inducing cell rescue from the apoptos is suffered in the absence of stimulation. Characterization of the sig naling pathways utilized by beta gamma interleukin-2 receptors in rest ing T cells, indicated that pp56(lck), but not Jak1 or Jak3, is activa ted upon receptor triggering. Compelling evidence is presented indicat ing that phosphatidylinositol 3-kinase associates with the intermediat e affinity interleukin-2 receptor and is activated upon interleukin 2 addition. Bcl-x(L) gene was also found to be induced upon beta gamma i nterleukin-2 receptor stimulation, Finally, pharmacological inhibition of phosphatidylinositol 3-kinase blocked both interleukin-2-mediated bcl-x(L) induction and cell survival. We conclude that beta gamma inte rleukin-2 receptor mediates T cell survival via a phosphatidylinositol 3-kinase-dependent pathway, possibly involving pp56(lck) and bcl-x(L) as upstream and downstream effectors, respectively.