Drug-induced inhibition of insulin recognition by T-cells: the antirheumatic drug aurothiomalate inhibits MHC binding of insulin peptide

Previous work has shown that the Au(I) moiety of the antirheumatic drug dis odium aurothiomalate (Au(I)TM) can selectively inhibit the response of muri ne CD4(+) T-cell hybridomas to antigenic peptides containing two or more cy steine (Cys) residues. Here, we investigated the mechanism that underlies t he inhibitory effect of Au(I)TM on T-cell recognition of bovine insulin (BI ). We found that low concentrations of Au(I)TM (10 mu M) inhibited the BI-i nduced proliferation of bulk T-cells from BI-immunized BALB/c mice as well as the IL-2 release of A(b)- and Ad-restricted T-cell hybridoma clones. Au( I)TM was found to inhibit binding of the immunodominant BI peptide A1-14 to isolated MHC class II molecules. We suggest that Au(I) forms stable chelat e complexes with thiol groups of two Cys residues in the BI A1-14 peptide. Conceivably, formation of these metal-peptide complexes keeps the peptide i n a sterical conformation that cannot undergo binding to MHC class II molec ules, resulting in an inhibition of T-cell activation due to insufficient p eptide presentation. (C) 1999 Elsevier Science Ltd. All rights reserved.