Abstract

Objective: We studied how tolerance to GAD65 affected the development of autoimmunity to other ß-cell autoantigens (ß-CAAs) in GAD65-transgenic (GAD-tg) NOD mice.

Research Design and Methods: We used ELISPOT to characterize the frequency and functional phenotype of T cell responses to GAD65 and other ß-CAAs at different ages in GAD-tg mice and their NOD mouse littermates.

Results: In young GAD-tg mice, Th1 responses to GAD65's dominant determinants were 13% - 18% of those in young NOD mice. This coincided with a great reduction in Th1 responses to other ß-CAAs. Evidently, GAD65-reactive T cells are important for activating and/or expanding early autoreactivities in NOD mice. As GAD-tg mice aged, their T cell responses to GAD65 remained low, but they developed supernormal splenic and pancreatic lymph node T cell autoimmunity to other ß-CAAs. Apparently, the elimination/impairment of many GAD65-reactive T cells allowed other ß-CAA-reactive T cells to eventually expand to a greater extent, perhaps by reducing competition for APCs, or homeostatic proliferation in the target tissue, which may explain the GAD-tg mice's usual disease incidence.

Conclusions: Transgenically-induced reduction of GAD65 autoreactivity curtailed the development of early T cell responses to other ß-CAAs. However, later in life, ß-CAA-reactive T cells expanded to supernormal levels. These data suggest that early ß-cell autoreactivities are mutually dependent for support to activate and expand, while later in the disease process, autoantigen-specific T cell pools can expand autonomously. These findings have implications for understanding T1D immunopathogenesis and for designing antigen-based immunotherapeutics.