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*
Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; and
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
Nonobese diabetic (NOD) mice spontaneously develop insulitis and
destruction of pancreatic islet 
cells similar to type 1 diabetes
mellitis in humans. Insulitis also occurs in the BDC2.5 TCR transgenic
line of NOD mice that express the rearranged TCR 
- and -chain
genes of a diabetogenic NOD CD4 T cell clone. When activated with
syngeneic islet cells in culture, BDC2.5 T cells adoptively transfer
disease to NOD recipients, but the identity of the islet cell Ag
responsible for pathogenicity is not known. To characterize the
autoantigen(s) involved, BDC2.5 T cells were used to screen a
combinatorial peptide library arranged in a positional scanning format.
We identified more than 100 decapeptides that stimulate these T cells
at nanomolar concentrations; they are then capable of transferring
disease to NOD-scid mice. Surprisingly, some of the
peptides include sequences similar (8 of 10 residues) to those found
within the 528–539 fragment of glutamic acid decarboxylase 65.
Although this 12-mer glutamic acid decarboxylase 65 fragment is only
slightly stimulatory for BDC2.5 T cells (EC50 > 100
µM), a larger 16-mer fragment, 526–541, shows activity in the low
micromolar range (EC50 = 2.3 µM). Finally, T cells
from prediabetic NOD mice respond spontaneously to these peptide
analogs in culture; this finding validates them as being related to a
critical autoantigen involved in the etiology of spontaneous diabetes
and indicates that their further characterization is important for a
better understanding of underlying disease
mechanisms.
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