Identification and modulation of a naturally processed T cell epitope fromthe diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65)

T cell recognition of autoantigens is critical to progressive immune-mediat ed destruction of islet cells, which leads to autoimmune diabetes. We ident ified a naturally presented autoantigen from the human islet antigen glutam ic acid decarboxylase, 65-kDa isoform (GAD65), by using a combination of ch romatography and mass spectrometry of peptides bound by the type I diabetes (insulin-dependent diabetes mellitus, IDDM)-associated HLA-DR4 molecule. P eptides encompassing this epitope-stimulated GAD65-specific T cells from di abetic patients and a DR4-positive individual at high risk for developing I DDM, T cell responses were antagonized by altered peptide ligands containin g single amino acid modifications. This direct identification and manipulat ion of GAD65 epitope recognition provides an approach toward dissection of the complex CD4(+) T cell response in IDDM.