Determination of glutamic acid decarboxylase 65 peptides presented by the type I diabetes-associated HLA-DQ8 class II molecule identifies an immunogenic peptide motif

Particular HLA class II allelic sequences are associated with susceptibilit y to type I diabetes, To understand the mechanism, knowledge of the molecul ar nature of the specific TCR/peptide/class II interactions involved in the disease process is required. To this end, we have introduced the diabetes- associated human class II HLA-DQ8 allele (DQA1*0301/DQB1*0302) as a transge ne into mice and analyzed T cell responses restricted by this molecule to a n important Ag in human diabetes, human glutamic acid decarboxylase 65, Hyb ridomas were used to determine the particular peptides from this Ag present ed 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 rel evant features for peptides that are immunogenic to T cells when presented by HLA-DQ8, The major immunogenic epitopes of glutamic acid decarboxylase 6 5 do not contain a negatively charged residue that binds in the P9 pocket o f the HLA-DQ8 molecule. PBMC from HLA-DQ8(+) diabetic and nondiabetic indiv iduals respond to these peptides, confirming that the mouse model is a usef ul tool to define epitopes of autoantigens that are processed by human APC and recognized by human T cells.