Differential presentation of glutamic acid decarboxylase 65 (GAD65) T cellepitopes among HLA-DRB1*0401-positive individuals

Glutamic acid decarboxylase 65 (GAD65) is one of the major autoantigens in type 1 diabetes. We investigated whether there is variation in the processi ng of GAD65 epitopes between individuals with similar HLA backgrounds and w hether the processing characteristics of certain immunogenic epitopes are d ifferent in distinct APC subpopulations. Using DR401-restricted T cell hybr idomas specific for two immunogenic GAD65 epitopes (115-127 and 274-286), w e demonstrate an epitope-specific presentation pattern in human B-lymphobla stoid cell lines (B-LCL), When pulsed with the GAD protein, some DRB1*0401- positive B-LCL, which presented GAD65 274-286 epitope efficiently, were una ble to present the GAD65 115-127 epitope, However, all B-LCL presented synt hetic peptides corresponding to either GAD epitope. In addition, when pulse d with human serum albumin, all cell lines gave equal stimulation of a DR4- restricted human serum albumin-specific T hybridoma, GAD65-transfected cell lines displayed the same presentation phenotype, showing that lack of the presentation of the 115-127 epitope was not due to inefficient uptake of th e protein. Blood mononuclear adherent cells, B cells, or dendritic cells de rived from the same individual displayed the same presentation pattern as o bserved in B cell lines, suggesting that the defect most likely is genetica lly determined. Therefore, individual differences in Ag processing may resu lt in the presentation of distinct set of peptides derived from an autoanti gen such as GAD65, This may be an important mechanism for the deviation of the immune response either into a regulatory pathway or into an inflammator y autoimmune reactivity.