LFA-1-MEDIATED COSTIMULATION

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DESCRIPTION: Antigen presentation to T cells requires the formation of a stable complex between the T cell and an antigen presenting cell (APC). The formation of and stability of this complex is controlled by adhesion molecules, most notably LFA-1. This complex provides for both intercellular and intracellular protein:protein interactions to take place that are essential to T cell activation. The investigators' preliminary results show that in addition to its role as an adhesion molecule, LFA-1 can function as a costimulatory molecule. This functional effect of LFA-1 on T cell activation can be detected by the induction of IL-2 gene expression and the down regulation of secondary IL-4 responses. In addition, co-engagement of LFA-1 can alter the composition of proteins recruited to the adhesion complex that forms at the site of T cell:APC interaction. The overall goal of this application is to determine whether the recruitment of these proteins, or the possible role of LFA-1 in directing the organization of proteins within the adhesion complex, impacts on the costimulatory function of LFA-1. They will dissect the distinct structural features of the CD18 cytosolic tail that impart various functions of LFA-1 by site directed mutagenesis and gene transfer. By segregating specific functions, they hope to discern whether the structural organization of the adhesion complex plays an integral role in LFA-1 function and in T-cell activation in general. They will do this through three Specific Aims: Aim 1: Determine the structural features of LFA-1 that mediate T cell costimulation. Aim 2: Determine the role of LFA-1 in the structural organization of the T cell:APC adhesion complex. Aim 3: Determine whether beta1 (VLA-4) and beta2 (LFA-1) integrins are functionally equivalent in T cell costimulation.