Increased in vivo frequency of IA-2 peptide-reactive IFNgamma+/IL-4- T cells in type 1 diabetic subjects.
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.
Herzog
Bernhard A
BA
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Ott
Patrick A
PA
Dittrich
Marcus T
MT
Quast
Stefan
S
Karulin
Alexey Y
AY
Kalbacher
Hubert
H
Karges
Wolfram
W
Tary-Lehmann
Magdalena
M
Lehmann
Paul V
PV
Boehm
Bernhard O
BO
Durinovic-Belló
Ivana
I
D000328:Adult; D001324:Autoantigens; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology
D001324:Autoantigens; D008565:Membrane Proteins; D010446:Peptide Fragments; D015847:Interleukin-4; D007371:Interferon-gamma; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8