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T-Cell Epitope Analysis on the Autoantigen Phogrin (IA-2ß) in the Nonobese Diabetic Mouse

Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado

The protein tyrosine phosphatases (PTPs) IA-2 and phogrin (IA-2ß) are major autoantigens in type 1 diabetes that possess common serological epitopes in their COOH termini. The epitopes recognized by the T-cells that cause the disease, however, remain to be defined. Eight phogrin-specific T-cell clones were generated from NOD mice, and their epitopes were mapped. The mapping was performed initially with recombinant gluthathione S-transferase–phogrin COOH deletion constructs and ultimately with overlapping synthetic peptides. Two dominant epitopes were identified: one (aa 629–649) immediately adjacent to the transmembrane domain (aa 604–628) and the second (aa 755–777) lying in the NH₂-terminal region of the conserved PTP domain. T-cells that are specific to either of these peptides and that could destroy islet tissue in vivo though spontaneous T-cell proliferative responses were observed in prediabetic female NOD splenocytes only to the aa 755–777 epitope. In NOD female mice immunized with the epitope peptide, intramolecular determinant spreading occurred from the aa 629–649 epitope to the aa 755–777 epitope but not in the opposite direction. We concluded that the initial T-cell response to phogrin is restricted to a small number of dominant peptides and that it subsequently spreads to other regions of the molecule, including those containing the major humoral epitopes that are highly conserved between IA-2 and phogrin.

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