Herzog, B. A., P. A. Ott, M. T. Dittrich, S. Quast, A. Y. Karulin, H. Kalbacher, W. Karges, M. Tary-Lehmann, P. V. Lehmann, B. O. Boehm, and I. Durinovic-Bello. 2004. Increased in vivo frequency of IA-2 peptide-reactive IFNgamma+/IL-4- T cells in type 1 diabetic subjects. J. Autoimmun. 23:45.

Categories: Autoimmunity, Working with Peptides and Peptide Pools

Keywords: Adult / Autoantigens / Diabetes Mellitus,Type 1 / immunology / metabolism / Female / Humans / Interferon Type II / Interleukin-4 / Male / Membrane Proteins / Peptide Fragments / Protein-Tyrosine-Phosphatase / Research Support,Non-U.S.Gov't / Research Support,U.S.Gov't,P.H.S. / T-Lymphocyte Subsets / T-Lymphocytes / Th1 Cells

Abstract: Active T cell recognition of islet antigens has been postulated as the pathogenic mechanism in human type 1 diabetes, but evidence is scarce. If T cells are engaged, they are expected to display increased clonal size and exhibit a T helper (Th)1/Th2 differentiation state. We used a peptide library that covers tyrosine phosphatase IA-2, a target antigen expressed in pancreatic beta cells, to probe 8 diabetic patients and 5 HLA-matched controls. When tested in a high resolution IFNgamma/IL-4 double color ELISPOT assay directly ex vivo, the number of IA-2-reactive IFNgamma producing cells was 17-fold higher in patients than in controls and IL-4 producing cells were not present. An average of 9 peptides was recognized in the patients vs. one in the controls. Determinant recognition primarily involved CD4+ cells and showed high variability among the patients. Furthermore, anti-CD28 antibody signal enhances quantitative assessment of effector T cells in T1D patients. In vitro expansion with peptides and IL-2 results in detection of responding cells in the controls and loss of disease specificity of the T cell response. Together these data provide strong evidence for the active targeting of IA-2 by Th1 memory effector cells in human type 1 diabetes.