The T Cell Response to Glutamic Acid Decarboxylase 65 in T Cell Receptor Transgenic NOD Mice

Using BW 5147 T cell hybridomas isolated by fusion with spleen and lymph node cells from NOD female mice, two T cell receptor transgenic NOD mouse lines were produced. Both TCR transgenics respond to their cognate peptide/MHC (GAD65 206-220 and 286-300) and produce IL-2, IFN-gamma, and small amounts of IL-10. Unexpectedly, the transgenic mice do not develop diabetes and have no insulitis. Analysis with a GAD65 286-300/I-A(g7) tetramer reveals that transgenic T cells are negatively selected in the thymus and further negatively selected in the periphery. When crossed to the C(alpha)(-/-) NOD line, CD4 T cells were reduced by 90% in the thymus and periphery. Further, the tetramer positive GAD65 286-300 specific T cells were capable of delaying the onset of diabetes in a standard transfer system. Thus, GAD65 specific TCR transgenic T cells (1) must express a second a chain to survive negative selection, (2) produce IL-2 and IFN-gamma, and (3) have a mildly protective effect on transfer of diabetes with diabetogenic spleen cells.