Insulin-dependent diabetes mellitus (IDDM) is a chronic autoimmune disease involving the selective destruction of the insulin-producing beta cells of the islets. Although a variety of host genetic factors contribute to disease susceptibility, progression to disease requires activated T cells. The relatively low frequency of IDDM may in part reflect that mature autoreactive T cells are normally subject to stringent immunoregulation. To gain information on the factors controlling immunoregulation, we propose to study the types of T-APC interactions that generate CD4+ T cells that have the ability to mediate IDDM in a murine transgenic model of disease. Our major goal is to test the hypothesis that the avidity of T-APC interactions plays a role in determining the outcome of mature T cell activation by directing the expression of accessory molecules on T cells and APC that influence the expression of particular effector functions.
In AIM 1, we will examine the extent to which antigen concentration and affinity of T-APC interactions dictate the expression of a variety of molecules regulating different aspects of T cell responses, e.g., costimulation, survival, homing.
In AIM 2, using both in vivo and in vitro models, we will define the role of antigen concentration and affinity in determining a) the cytokines produced by the effector T cells, b) the extent of the proliferative response, and c) the susceptibility of those T cells to tolerance.
In AIM 3, the influence of avidity in generating T cells that migrate to the pancreas and display destructive or protective effects on the islets will be determined. Collectively, the experiments will provide a comprehensive view of how the avidity of T-APC interactions can influence the generation of potential autoaggressive cells and define the particular steps between recognition of antigen and disease that are most sensitive to changes in avidity. The information gained from these studies may contribute to the development of both effective intervention strategies and strategies for monitoring the effectiveness of intervention.
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