Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects.
Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is recognized as a major autoantigen for autoimmune type 1 diabetes (T1D) in the NOD mouse model. This study was undertaken to examine CD4+ T cell responses toward IGRP in human subjects. The tetramer-guided epitope mapping approach was used to identify IGRP-specific CD4+ T cell epitopes. IGRP(23-35) and IGRP(247-259) were identified as DRA1*0101/DRB1*0401-restricted epitopes. IGRP(13-25) and IGRP(226-238) were identified as DRA1*0101/DRB1*0301-restricted epitopes. IGRP-specific tetramers were used to evaluate the prevalence of IGRP-reactive T cells in healthy and T1D subjects. More than 80% of subjects with either DRB1*0401 or DRB1*0301 haplotype have IGRP-specific CD4+ T cell responses for at least one IGRP epitope. IGRP-specific T cells from both healthy and T1D groups produce both gamma-IFN and IL-10. DRA1*0101/DRB1*0401 IGRP(247-259)-restricted T cells also show cross-reactivity to an epitope derived from liver/kidney glucose-6-phosphatase. The detection of IGRP-reactive T cells in both type 1 diabetic subjects and healthy subjects and recent reports of other autoreactive T cells detected in healthy subjects underscore the prevalence of potentially autoreactive T cells in the peripheral immune system of the general population.
Yang
Junbao
J
Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
Danke
Nancy A
NA
Berger
DeAnna
D
Reichstetter
Sandra
S
Reijonen
Helena
H
Greenbaum
Carla
C
Pihoker
Catherine
C
James
Eddie A
EA
Kwok
William W
WW
D000328:Adult; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D020134:Catalytic Domain / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005952:Glucose-6-Phosphatase / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics; D015803:HLA-DR3 Antigen; D006239:Haplotypes; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology* / Q000276:immunology*; D008969:Molecular Sequence Data
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; C500432:HLA-DR0301 antigen; D015803:HLA-DR3 Antigen; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human