The role of MHC class II molecules in type I diabetes: An analysis of presentation of glutamic acid decarboxylase 65 by the diabetes-associated HLA-DQ8 molecule

Type I diabetes is a disease that results from autoimmune-mediated destruction of beta-cells in pancreatic islets that produce insulin. Particular HLA class II allelic sequences are associated with susceptibility to type I diabetes. We postulated that knowledge of the molecular nature of the relevant TCR/peptide/class II interactions might lead to an understanding of the mechanism by which certain class II allele products lead to disease susceptibility. To this end, we have generated transgenic mouse models expressing the diabetes-associated human class II HLA-DQ8 (DQA1*0301/DQB1*0302) molecule, and the closely related HLA-DQ7 (DQA1*0301/DQB1*0301) molecule, which is not associated with disease susceptibility. We have used the transgenic models to analyze T cell responses restricted by these molecules to an important antigen in human diabetes, human glutamic acid decarboxylase 65 kD. Hybridomas were used to determine the particular peptides from this antigen presented by HLA-DQ8 to T cells, and to map the core minimal epitopes required for T cell stimulation. Analysis of these core epitopes reveals a motif and relevant features for peptides that are immunogenic to T cells when presented by HLA-DQ8. The major immunogenic epitopes of glutamic acid decarboxylase 65 kD do not contain a negatively charged residue that binds in the P9 pocket of the HLA-DQ8 molecule. The peptides may bind with a relatively low affinity to the HLA-DQ8 molecule. The HLA-DQ8 molecule has unusual features associated with disease susceptibility that may interact with unique aspects of these peptides. PBMC from HLA-DQ8 + diabetic and non-diabetic individuals respond to these peptides, confirming that the mouse model is a useful tool to define epitopes of autoantigens that are processed by human APC and recognized by human T cells.