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 Citations (Scopus)

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
StatePublished - Mar 15 2004
Externally publishedYes

Fingerprint

Prediabetic State
T-Lymphocytes
Peptides
Inbred NOD Mouse
To autoantigen
HLA-DQ8 antigen
T-Lymphocyte Epitopes
Autoantigens
Hybridomas
HLA-DR Antigens
Type 1 Diabetes Mellitus
Islets of Langerhans
Alanine
Haplotypes
Transgenic Mice
Interleukin-2
Epitopes

ASJC Scopus subject areas

  • Immunology

Cite this

Kelemen, K., Gottlieb, P. A., Putnam, A. L., Davidson, H. W., Wegmann, D. R., & Hutton, J. C. (2004). HLA-DQ8-Associated T Cell Responses to the Diabetes Autoantigen Phogrin (IA-2β) in Human Prediabetes. Journal of Immunology, 172(6), 3955-3962.

HLA-DQ8-Associated T Cell Responses to the Diabetes Autoantigen Phogrin (IA-2β) in Human Prediabetes. / Kelemen, Katalin; Gottlieb, Peter A.; Putnam, Amy L.; Davidson, Howard W.; Wegmann, Dale R.; Hutton, John C.

In: Journal of Immunology, Vol. 172, No. 6, 15.03.2004, p. 3955-3962.

Research output: Contribution to journalArticle

Kelemen, K, Gottlieb, PA, Putnam, AL, Davidson, HW, Wegmann, DR & Hutton, JC 2004, 'HLA-DQ8-Associated T Cell Responses to the Diabetes Autoantigen Phogrin (IA-2β) in Human Prediabetes', Journal of Immunology, vol. 172, no. 6, pp. 3955-3962.
Kelemen K, Gottlieb PA, Putnam AL, Davidson HW, Wegmann DR, Hutton JC. HLA-DQ8-Associated T Cell Responses to the Diabetes Autoantigen Phogrin (IA-2β) in Human Prediabetes. Journal of Immunology. 2004 Mar 15;172(6):3955-3962.
Kelemen, Katalin ; Gottlieb, Peter A. ; Putnam, Amy L. ; Davidson, Howard W. ; Wegmann, Dale R. ; Hutton, John C. / HLA-DQ8-Associated T Cell Responses to the Diabetes Autoantigen Phogrin (IA-2β) in Human Prediabetes. In: Journal of Immunology. 2004 ; Vol. 172, No. 6. pp. 3955-3962.
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