Autoimmune T-cell responses to peptide determinants of several autoantigens have recently been characterized. These data suggest that, in some autoimmune models, such as experimental autoimmune encephalomyelitis, T-cell responses may diversify from a nested set of peptides to include many other peptide regions. A similar immune phenomenon pertaining to autoimmune diabetes (IDDM) is observed in NOD mice. We have explored a similar pattern of T-cell responses related to age and disease status in NOD mice termed epitope dominance, which describes immune responses toward a pronounced subset of determinants of the autoantigen glutamic acid decarboxylase (GAD). Our studies have identified a total of five GAD epitopes between the 65 and 67 kDa isoforms. The magnitude of T-cell responses to these various determinants was dependent on the stage of disease as well as on whether mice were protected from disease. The T-cell responses of these epitopes in NOD mice correlated with the predicted binding of these peptides to the NOD class II molecule I-Ag7. We therefore propose a model which implicates antigen presenting cells as critical entities in the propagation of dominant responses to the presentation of autoantigens to T cells, particularly in the Th 1 environment of the NOD mouse. This hypothesis presents a new framework for the discussion and interpretation of the kinetics of T-cell responses to different peptide epitopes in autoimmune diseases such as IDDM.