Our objective in this project is to define the effector function of diabetogenic CD4 Th1 T cells through the investigation of the cytokines and chemokines they express and determine how these mediators contribute to pathogenesis in the autoimmune NOD model of type 1 diabetes. We hypothesize that macrophage recruitment and activation is a key component of CD4 Th1 T cell effector function and that TNFa in particular has a central role in this process. Our specific aims are to: (1) use a panel of T cell clones and T cells from TCR-Tg mice to determine the cytokines and chemokines necessary for the effector function of diabetogenic CD4+ Th1 T cells;(2) determine whether the pathogenic effects of CD4+ Th1 T cells are dependent on the effector function of the macrophages recruited and stimulated by Th1 T cells;and (3) investigate whether TNFa secretion by diabetogenic CD4 T cells is necessary for induction of disease. The significance of these studies lies in the fact that a major goal of immunotherapy for autoimmune disease is to specifically target certain T cell subsets. 1 way to direct therapy to T cells is to target specific molecules that govern T cell effector function. Our data suggests that pathogenic Th1 T cells may have distinctive functional characteristics and our goal is to further define these properties using Th1 T cell clones that can be studied separately, in the absence of other T cells, or in the presence of defined T cells. A more complete understanding of the effector function of Th1 T cell subsets will help us design more specific approaches to T cell targeted immunotherapy.

R01DK050561

1996-09-01

2011-06-30