Abstract

A diabetic T cell clone, BDC2.5, reacts to a GAD65‐mimicking peptide in the picomolar range, but remains unresponsive to all GAD65 peptides tested. However, APC from GAD65‐primed non‐obese diabetic (NOD) mice were found effective in presenting a native GAD65 peptide, p524–543, to stimulate this clone (Dai et al. JI 175:3621). Mouse beta cell lines express different levels of GAD65 protein, and vary in stimulating BDC2.5 T cells. Surprisingly, overexpression of GAD65 in one beta cell line increased its antigenicity over 100‐fold in stimulating the T cells, whereas control plasmids had no effect; mutagenesis within the GAD65 plasmids confirmed that the same region, p524–543, is essential for the enhanced stimulation of BDC2.5 cells, and a mutation outside this region was ineffective. Synthetic peptides covering different sequences within p524–543 were non‐stimulatory for the T cells; however, a single replacement, K534W, within this peptide was sufficient to convert the non‐stimulatory native peptide to a strong agonist that activates BDC2.5 cells at 1.0 μg/ml. These data suggest that unique intracellular events occur to GAD65 molecule after its transcription or translation, which result in altered processing and presentation of otherwise tolerogenic T cell determinants and thus activating diabetogenic T cells, such as BDC2.5. (Supported by grants from NIH, JDRF and DNRG to EES)

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