HLA-DQ-regulated T-cell responses to islet cell autoantigens insulin and GAD65.
HLA-DQ is strongly associated with genetic predisposition to type 1 diabetes. It is assumed that HLA-DQ molecules exert their effects on the disease via the presentation of peptides from islet autoantigens to CD4(+) T-cells, but little information regarding HLA-DQ-restricted, islet antigen-specific, autoreactive T-cells is available. To investigate the role of HLA-DQ in the immune response to islet autoantigens, we measured T-cell proliferation to insulin and GAD65 in the presence and absence of monoclonal antibodies that block HLA-DQ-mediated antigen presentation in recent-onset type 1 diabetic patients and their siblings. Positive proliferative T-cell responses to GAD65 were observed in 60% of type 1 diabetic patients and 52% of siblings. This proliferation was significantly reduced in the presence of anti-DQ antibody, demonstrating the presence of primed, effector HLA-DQ-restricted T-cell responses to GAD65. Positive proliferative responses to insulin were observed in 25% of type 1 diabetic patients and 10% of siblings. However, blocking HLA-DQ-restricted T-cell responses led to a significant increase in proliferation to insulin, implying the presence of primed suppressive HLA-DQ-restricted T-cell responses to insulin. These results indicate that HLA-DQ acts as a restriction element for both proliferative and suppressor cells, with the relative balance of these cells dependent on the nature of the autoantigen.
Tree
Timothy I M
TI
Department of Immunology, Guy's, King's, and St. Thomas' School of Medicine, Denmark Hill Campus, Rayne Institute, London, UK.
Duinkerken
Gaby
G
Willemen
Sabine
S
de Vries
René R P
RR
Roep
Bart O
BO
D000483:Alleles; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation; D001324:Autoantigens / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000494:pharmacology*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000276:immunology*; D007527:Isoenzymes / Q000494:pharmacology*; D008297:Male; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013745:Tetanus Toxoid / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D006683:HLA-DQ Antigens; D007328:Insulin; D007527:Isoenzymes; D013745:Tetanus Toxoid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2