Mechanism of T Cell Receptor Mediated Activation of NFkappaB

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Activation of the transcription factor NF-kappaB after engagement of the T cell receptor (TCR) is important for T cell proliferation and activation during the adaptive immune response. Recent reports have described a signaling pathway that involves the kinase PKCtheta, the scaffold protein CARD11 (also called CARMA-1), the CARD-domain containing protein BcMO, and the paracaspase (protease related to caspases) MALT1 as critical intermediates linking the TCR to the IkappaB kinase (IKK) complex. However, the exact sequence of events that occurs following the activation of this signaling pathway remains poorly defined. We have recently demonstrated that 3-phosphoinositide-dependent kinase 1 (PDK1) has an essential role in this pathway by regulating the activation of PKCtheta and through signal-dependent recruiting of both PKCtheta and CARD11 to lipid rafts. PDK1-associated PKCq recruits the IKKcomplex, whereas PDK1-associated CARD11 recruits the Bcl10-MALT1 complex, thereby allowing activation of the IKK complex through Bcl10-MALT1-dependent ubiquitination of the IKK complex subunit known as NEMO. Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-kappaB activation pathway in T cells. In this proposal we will further extend our observations to better understand exactly how PDK-1 recruits PKCtheta and CARD11. We will identify the domains involved in these interactions and use the knowledge from these studies to devise novel approaches for suppressing T-cell activation. In addition we have also found that PKCtheta is involved in the activation of LFA1 following TCR-engagement through an inside-out pathway. We will establish the importance of this pathway by generating novel genetic models that we believe will dissociate the ability of PKCtheta to function as an adapter for recruitment of IKK, from its ability to promote stable conjugation and immunological synapses through its effect on LFA1. We believe that these studies will both provide a fuller understanding of a key cellular pathway, and the opportunity to develop novel approaches for immunosuppression.