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

Katalin Kelemen, Dale R. Wegmann, John C. Hutton

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The protein tyrosine phosphatases (PTPs) IA-2 and phogrin (IA-2β) 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.

Original languageEnglish (US)
Pages (from-to)1729-1734
Number of pages6
JournalDiabetes
Volume50
Issue number8
DOIs
StatePublished - Aug 2001

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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