CD4+ T lymphocytes are critically important to the host for cell- mediated immunity and regulation of antibody production. The broad objectives of this proposal are to gain a better understanding of the activation requirements of these cells with the hope of applying this information to the development of specific immunosuppressive regimens. Previous work demonstrated that proliferation by virgin, primed, or cloned murine Th1 T cells is not induced by certain fixed antigen-presenting cells (APC) or Ia molecule-containing planar lipid membranes. Proliferation is restored under these conditions by the addition of allogeneic accessory cells that can not be recognized by the idiotypic T cell receptors (Ti) on the responding T cells, demonstrating the in- volvement of an APC-derived costimulatory activity in T cell activation. In addition, Th1 clones stimulated by Ti occupancy without costimulatory signals results in the active induction of unresponsiveness to normal antigen stimulation. The costimulatory property of APC will be further explored in this proposal by: (a) examining the effects of costimulatory activity on early biochemical second messengers generated in the T cell through the Ti complex, (b) purifying various accessory cell populations and comparing their ability to provide costimulation with their capacity to act as APC, (c) studying the induction of costimulatory activity by activating accessory cells with various mediators, (d) preparing monoclonal antibodies to aid in the biochemical characterization of costimulatory molecules, and (e) attempting to induce specific T cell unresponsiveness in a graft-versus-host- disease situation by inactivating alloreactive T cells with costimulation-deficient APC. Attainment of these objectives would provide a framework for manipulating the immune response in a specific fashion with potential application to control of deleterious T cell reactivity as in graft rejection
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