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INSULIN-DEPENDENT diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice results from the T-lymphocyte-mediated destruction of the insulin-producing pancreatic β-cells and serves as a model for human IDDM¹. Whereas a number of autoantibodies are associated with IDDM², it is unclear when and to what β-cell antigens pathogenic T cells become activated during the disease process. We report here that a T-helper-1 (Thl) response to glutamate decarboxylase develops in NOD mice at the same time as the onset of insulitis. This response is initially limited to a confined region of glutamate decarboxylase, but later spreads intramolecularly to additional determinants. Subsequently, T-cell reactivity arises to other β-cell antigens, consistent with intermolecular diversification of the response. Prevention of the spontaneous anti-glutamate decarboxylase response, by tolerization of glutamate decarboxylase …