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

16 Citations (Scopus)

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 - Jan 1 2001
Externally publishedYes

Fingerprint

Inbred NOD Mouse
T-Lymphocyte Epitopes
Autoantigens
Epitopes
T-Lymphocytes
Peptides
Class 8 Receptor-Like Protein Tyrosine Phosphatases
Protein Tyrosine Phosphatases
Glutathione Transferase
Type 1 Diabetes Mellitus
Clone Cells

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

T-Cell Epitope Analysis on the Autoantigen Phogrin (IA-2β) in the Nonobese Diabetic Mouse. / Kelemen, Katalin; Wegmann, Dale R.; Hutton, John C.

In: Diabetes, Vol. 50, No. 8, 01.01.2001, p. 1729-1734.

Research output: Contribution to journalArticle

Kelemen, Katalin ; Wegmann, Dale R. ; Hutton, John C. / T-Cell Epitope Analysis on the Autoantigen Phogrin (IA-2β) in the Nonobese Diabetic Mouse. In: Diabetes. 2001 ; Vol. 50, No. 8. pp. 1729-1734.
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