FUNCTIONAL CONSEQUENCES OF COSTIMULATION THROUGH LFA-1

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LFA-1 is a well recognized adhesion molecule, that plays an important role in T cell activation and homing. In addition, LFA-1 has been implicated in providing co-stimulatory signals that can work in concert with signals transduced through the TcR complex to initiate T cell activation. We have recently found that, when co-stimulation is limited to LFA-1/ICAM-1 interactions, antigen presentation efficiently drives CD4+ T cells into the cell cycle, but these cells ultimately die of apoptosis. T cell survival can be restored by supplementation with normal levels of exogenous IL-2 or by restimulation with antigen presented by B7-1+ antigen presenting cells. In both cases, when these T cells have been primed with antigen in the context of LFA-1 co-stimulation are tested for their ability to produce cytokines, they secrete normal levels of IL-2 and IFN-gamma, but do not secrete detectable levels of IL-2. These data suggest that if naive T cells first encounter antigen on APC that express ICAM-1, but not B7 (for example, non-hematopoietic cells induced to express class II and ICAM-1), they will be skewed toward Th1-type proposal are to assess the cellular and molecular events that determine the cytokine potential of T cells that are primed with antigen in the context of LFA-1 co-stimulation and to evaluate the immunoregulatory potential of these T cells in vivo. We will do this through three specific aims. Specific Aim 1: Determine how different co-stimulatory molecules regulate the survival and differentiation of CD4+ T cells primed by antigen in the presence of LFA-1/ICAM-1 interactions. Specific Aim 2: Analyze the molecular events that account for the failure to express IL-4 after T cells have been primed in the context of LFA-1-mediated co-stimulation. Specific Aim 3: Assess the role of LFA-1 co-stimulation in Th1 subset skewing using freshly isolated APC and in vivo T cell responses.