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HLA-DQ–Regulated T-Cell Responses to Islet Cell Autoantigens Insulin and GAD65

¹ Department of Immunology, Guy’s, King’s, and St. Thomas’ School of Medicine, Denmark Hill Campus, Rayne Institute, London, U.K
² Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, the Netherlands

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.

Abbreviations: MHC, major histocompatibility complex; SI, stimulation index

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