Regulation of the T Cell Cytoskeleton by Costimulation

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DESCRIPTION (provided by the applicant): T cells are the central regulatory cells of the adaptive immune system. For their complete activation recognition of the antigenic peptide/MHC complex by the TCR has to be complemented by engagement of accessory receptors. This phenomenon is called costimulation. The most prominent accessory receptors are CD28 and LFA-1. Costimulation is medically relevant as interference with costimulation, in particular with CD28 and LFA-1 has proven to be therapeutically useful in the treatment of cancer and autoimmune diseases. At the cellular level CD28 and LFA-1 mediate effector cytokine secretion and regulate T cell cytoskeletal rearrangements. The rearrangements are crucial for the assembly of a signaling complex that mediates efficient T cell activation. While signal transduction in the regulation of effector cytokine secretion has been extensively studied, the mechanism of the cytoskeletal regulation is unknown. We propose to address this question here. Using a recently developed video fluorescence microscopy approach, we propose to identify the location of ligand-engaged CD28 and LFA-1 at the same time as that of the ligand-engaged TCR or that of actin. This will contribute to an improved understanding of the mechanism of costimulation. In addition, we propose to identify the most proximal effector proteins of CD28 and LFA-1 regulating the T cell cytoskeletal rearrangements. An improved understanding of costimulation should significantly contribute to the treatment of cancer and autoimmune diseases.