Insulin reactive Type B T cells escape negative selection and are diabetogenic (48.11)

Abstract

Abstract Several autoantigens thought to play a role in type 1 diabetes pathogenesis have been implicated, one of which, insulin, has been extensively associated with onset of disease. In particular, the peptide spanning the residues 9-23 of the insulin beta chain bound to the MHC class II allele, I-Ag7, has been characterized as the dominant epitope in NOD mice for islet infiltrating insulin specific CD4+ T cells. Intriguingly, the majority but not all of autoreactive T cells that recognize insulin are deleted during development in the thymus. In an effort to figure out why certain autoreactive T cells escape selection we have a found a unique population of insulin reactive T cells that recognize the peptide fragment 9-23 given exogenously (type B) but are unable to recognize processed native protein (type A). These type B insulin reactive T cells escape negative selection during development and can be elicited by peptide immunization. Primary lines derived from these T cells proliferated when cocultured with ex vivo isolated beta cells suggesting that dendritic cells present in islets constituitively present the type B conformer of the 9-23 epitope of insulin. Finally, primary lines were capable of inducing diabetes when adoptively transferred into NOD.scid recipients. These results suggest T cells that recognize type B conformers of self proteins escape negative selection and have the capacity to induce autoimmunity.