T-cell lines reactive to an immunodominant epitope of the tyrosine phosphatase-like autoantigen IA-2 in type 1 diabetes.
Type 1 diabetes is the result of destruction of the insulin-secreting beta-cells of the pancreas by a process in which T-cells play a central role. A tyrosine phosphatase-like protein, IA-2, is a major target for autoantibodies and T-cells in the disease. In this study, we have further characterized the T-cell response to IA-2 by the generation and characterization of T-cell lines. T-cell lines responsive to IA-2 antigen were generated from 17 of 32 patients and 3 of 10 control subjects. Antigen specificity was confirmed in lines from six diabetic patients and one control individual by demonstration of responses to synthetic IA-2 peptides and epitope mapping. Five lines from diabetic patients responded to one of two peptides representing amino acids 831-850 and 841-860 of IA-2. The overlapping portion may therefore represent an immunodominant region of the molecule. The sixth patient-derived line responded to a peptide representing amino acids 751-770 of IA-2 presented by the DR 4 (DRB1*0401) allele that confers susceptibility to type 1 diabetes. Primary T-cell responses to peptides of the immunodominant region were detected in 9 of 19 (47%) type 1 diabetic patients and 16 of 22 (73%) nondiabetic siblings, consistent with this region having immunostimulatory properties. The study reports for the first time T-cell lines reactive to IA-2 from diabetic patients and defines an immunodominant region of the molecule.
Hawkes
C J
CJ
Department of Medicine, Guy's, King's College and St Thomas' School of Medicine, London, UK.
Schloot
N C
NC
Marks
J
J
Willemen
S J
SJ
Drijfhout
J W
JW
Mayer
E K
EK
Christie
M R
MR
Roep
B O
BO
D000293:Adolescent; D001324:Autoantigens / Q000276:immunology*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes; D005260:Female; D006680:HLA Antigens / Q000032:analysis; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D007223:Infant; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D000939:Epitopes; D006680:HLA Antigens; D016056:Immunodominant Epitopes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; C516862:PTPRN protein, human; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8