HLA-DR53 molecules restrict glutamic acid decarboxylase peptide presentation to T cells of a Type I diabetes patient: specification of the trimolecular HLA-peptide/T-cell receptor complex

Aims/hypothesis. Our aim was to define the molecular specificity of glutami c acid decarboxylase-specific T-cells isolated from a patient (patient 40) with recent onset Type I (insulin-depent) diabetes mellitus. Methods. The p eptide epitope was defined using synthetic peptides to identify the minimal sequence required for T-cell activation and to determine the amino acids t hat contribute either to MHC binding or T-cell receptor signaling. The MHC class II-restricted peptide presentation was determined using a panel of al logeneic antigen-presenting cells and murine fibroblast-cell lines transfec ted to express individual human class II alleles and by blocking studies wi th monoclonal antibodies. The T-cell receptor was also molecularly characte rized. Results. Despite that patient 40 carries high-risk alleles of the DR B1 and DQB1 loci, his T-cells recognize a glutamic acid decarboxylase-deriv ed peptide in association with class II, DR53, molecules. Although anchor r esidues for DR53 molecules have not yet been determined, it was possible to model epitope binding based on sequence comparisons with other class II mo lecules associated with susceptibility or protection for Type I diabetes. Conclusion/interpretation. The complete molecular specification of the MHC- peptide ligand and the T-cell receptor complex of glutamic acid decarboxyla se-specific T-cells will enable analysis of strategies designed to alter T- cell function. For example, the role of altered peptide ligands or T-cell r eceptor-specific peptides can be studied using a model whose components ref lect the natural affinities of MHC-peptide and T-cell receptor-ligand inter actions selected in response to this important autoantigen.