T-CELL ANTIGEN RECEPTOR ASSOCIATED SIGNALING

Signal transduction through the T cell receptor (TCR) is associated with the rapid activation of a variety of kinases that are of particular interest to this laboratory, including Lck, PKC-q, and Itk. As a T cell encounters cognate antigen, signaling complexes are repositioned to the interface of the antigen-presenting cell to form a highly organized supramolecular structure termed the "immunological synapse." PKC-q, for example, is the only member of the PKC family to undergo recruitment to the central region of the immunologic synapse, where it delivers activation signals that have not been fully characterized. From studies of mice genetically deficient in PKC-q, we have learned that PKC-q is required for TCR coupling to NF-kB and AP-1 in peripheral T cells. In the absence of PKC-q, T cells fail to transactivate IL-2 and to upregulate CD25 (the high affinity receptor for IL-2), resulting in greatly impaired proliferation. We are currently investigating the precise signaling pathways by which PKC-q transduces signals to transcription factors essential for effector T cell development.

We employ a wide variety of experimental approaches to gain new insights into signaling events associated with T cell activation and differentiation. We have generated gene-ablated mice to investigate, in vivo, the functions of PKC-q, Itk, Lck, RORg, Runx family members, and other mediators. We are utilizing gene microarrays to help define the specific gene targets of these cascades. We have developed gene-trapping vectors to allow us to perform cell-based screens to identify and characterize novel T cell transactivation cascades. In collaboration with Mike Dustin's lab, we have been performing microscopic studies of molecular reorganization events associated with cellular activation. We are also particularly interested in exploiting RNAi-based tools in our studies of T cell activation.

Selected Publications

   
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