The present study explored the consequences of phosphoinositide (3,4,5)-triphosphate [PI(3,4,5)P3] binding to the pleckstrin homology (PH) domain of the serine/threonine kinase 3-phosphoinositide-dependent kinase 1 (PDK1). The salient finding is that PDK1 directly transduces the PI(3,4,5)P3 signaling that determines T-cell trafficking programs but not T-cell growth and proliferation. The integrity of the PDK1 PH domain thus is not required for PDK1 catalytic activity or to support cell survival and the proliferation of thymic and peripheral T cells. However, a PDK1 mutant that cannot bind PI(3,4,5)P3 cannot trigger the signals that terminate the expression of the transcription factor KLF2 in activated T cells and cannot switch the chemokine and adhesion receptor profile of naïve T cells to the profile of effector T cells. The PDK1 PH domain also is required for the maximal activation of Akt/protein kinase B (PKB) and for the maximal phosphorylation and inactivation of Foxo family transcription factors in T cells. PI(3,4,5)P3 binding to PDK1 and the strength of PKB activity thus can dictate the nature of the T-cell response. Low levels of PKB activity can be sufficient for T-cell proliferation but insufficient to initiate the migratory program of effector T cells. Copyright © 2009, American Society for Microbiology. All Rights Reserved.