Phosphoinositide-dependent kinase 1 integrates T cell receptor and CD28 co-receptor signaling to effect NF-κB induction and T cell activation

In addition to T cell receptor (TCR) ligation, activation of CD28 coreceptor by costimulatory molecule B7 is required for transcription factor NF-κB induction and robust T cell activation, though exactly how CD28 contributes to this remains incompletely understood. We demonstrated here that phosphoinositide-dependent kinase 1 (PDK1) plays an essential role in integrating TCR and CD28 signals. Upon deletion of PDK1 in T cells, TCR-CD28 signals failed to induce NF-κB activation or protein kinase C θ (PKC-θ) phosphorylation, although T cell survival and pathways dependent on p38 and Jnk kinases or transcription factor NF-AT were unaffected. CD28 facilitated NF-κB activation by regulating PDK1 recruitment and phosphorylation, which are necessary for efficient binding of PDK1 to PKC-θ and CARMA1, and thus for NF-κB induction.