Glutamic acid decarboxylase-specific CD4+ regulatory T cells

It is known that CD4(+) regulatory T cells (Tr cells) play a central role in inducing immune tolerance in animals and humans. Compared to polyclonal Tr cells, autoantigen-specific Tr cells are more potent at blocking pathogenic immune responses. In order to better understand the role of Tr cells in controlling type 1 diabetes development and to help design effective antigen-specific cell-based therapeutic methods to treat the disease, it is necessary to: (a) determine the antigen specificity of Tr cells; (b) study how antigen-specific Tr cells behave in vivo; (c) investigate the interaction of Tr cells with pathogenic T cells (Tpath cells) and determine whether such interaction correlates with the progression or inhibition of diabetes; and (d) determine the cellular and molecular mechanisms underlying the regulation of diabetes by Tr cells. We have addressed these questions with a focus on the studies of glutamic acid decarboxylase (GAD)-specific T cells. Previous studies have suggested that GAD-specific T cells play a key role in type 1 diabetes. Treatment of NOD mice with GAD or its peptides can prevent the progression toward overt disease. The preventive effect could be due to either the deletion of antigen-specific pathogenic T cells or the induction of potent antigen-specific Tr cells. Using antigen-specific I-Ag7 tetramers we have isolated several populations of GAD peptide-specific T cells from diabetes-prone NOD and diabetes-resistant NOR mice. Herein, we summarize our studies on the role of these GAD peptide-specific T cells in type 1 diabetes. We present evidence that supports the hypothesis that the repertoire of T cells specific for these GAD peptides is biased toward Tr cells that inhibit diabetes rather than toward pathogenic T cells that induce diabetes.