HLA-DQ8-Associated T Cell Responses to the Diabetes Autoantigen Phogrin (IA-2β) in Human Prediabetes

Katalin Kelemen, Peter A. Gottlieb, Amy L. Putnam, Howard W. Davidson, Dale R. Wegmann, John C. Hutton

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Susceptibility to type 1A autoimmune diabetes is linked to expression of particular MHC class II molecules, notably HLA-DQ8 in man and the orthologous I-Ag7 in the nonobese diabetic mouse. In the present study, we analyzed two peptide epitopes (peptides 2 and 7) from the diabetes autoantigen phogrin (IA-2β), in the context of their presentation by the I-A g7 and HLA-DQ8 molecules and their role as potential T cell antigenic epitopes in human diabetes. Both of these peptides are targets of diabetogenic CD4+ T cell clones in the nonobese diabetic mouse. Transgenic mice expressing HLA-DQ8 as the sole class II molecule generated a robust T cell-proliferative response when primed with peptide 2 or peptide 7 in CFA. Analysis of the IL-2 secretion from peptide 2-reactive T cell hybridomas stimulated with alanine-substituted peptides identified three residues that were crucial to the response. Among 41 islet cell Ag-positive prediabetic human subjects, 36.5% showed PBMC-proliferative responses to peptide 7, 17.1% to peptide 2, and 17.1% to both peptides; no response was seen among 20 matched healthy controls. Stratification of the data based upon HLA haplotype suggested that peptide 7 could be presented by at least one HLA-DR molecule in addition to HLA-DQ8, a finding that was supported by blocking studies with monomorphic mAbs. The results indicate that common phogrin peptides are targeted by autoreactive T cells in human and murine type 1A diabetes, and that the responses may in part be associated with the similar peptide-binding specificities of I-Ag7 and HLA-DQ8.

Original languageEnglish (US)
Pages (from-to)3955-3962
Number of pages8
JournalJournal of Immunology
Volume172
Issue number6
DOIs
StatePublished - Mar 15 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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