An Altered Self-Peptide with Superagonist Activity Blocks a CD8-Mediated Mouse Model of Type 1 Diabetes

T cell tolerance can be experimentally induced through administration of self-peptides with single amino acid substitution (altered peptide ligands or APLs). However, little is known about the effects of APLs on already differentiated autoreactive CD8+ T cells that play a pivotal role in the pathogenesis of autoimmune diabetes. We generated a panel of APLs derived from an influenza virus hemagglutinin peptide exhibiting in vitro functions ranging from antagonism to superagonism on specific CD8+ T cells. A superagonist APL was further characterized for its therapeutic activity in a transgenic mouse model of type 1 diabetes. When injected i.v. 1 day after the transfer of diabetogenic hemagglutinin-specific CD8+ T cells into insulin promoter-hemagglutinin transgenic mice, the superagonist APL proved more effective than the native hemagglutinin peptide in blocking diabetes. This protective effect was associated with an inhibition of CD8+ T cell cytotoxicity in vivo and with a decreased accumulation of these cells in the pancreas, leading to a marked reduction of intrainsulitis. In conclusion, a superagonist "self-peptide" APL was more effective than the native peptide in treating a CD8+ T cell-mediated diabetes model.