Progression of autoimmune diabetes driven by avidity maturation of a T-cell population

For unknown reasons, autoimmune diseases such as type 1 diabetes develop af ter prolonged periods of inflammation of mononuclear cells in target tissue s 1. Here we show that progression of pancreatic islet inflammation to over t diabetes in nonobese diabetic (NOD) mice is driven by the 'avidity matura tion' of a prevailing, pancreatic beta-cell-specirc T-lymphocyte population carrying the CD8 antigen. This T-lymphocyte population recognizes two rela ted peptides (NRP and NRP-A7)(2) in the context of H-2K(d) class I molecule s of the major histocompatibility complex (MHC). As pre-diabetic NOD mice a ge, their islet-associated CD8(+) T lymphocytes contain increasing numbers of NRP-A7-reactive cells, and these cells bind NRP-A7/H-2K(d) tetramers wit h increased specificity, increased avidity and longer half-lives. Repeated treatment of pre-diabetic NOD mice with soluble NRP-A7 peptide blunts the a vidity maturation of the NRP-A7-reactive CD8(+) T-cell population by select ively deleting those clonotypes expressing T-cell receptors with the highes t affinity and lowest dissociation rates for peptide-MHC binding. This inhi bits the local production of T cells that are cytotoxic to beta cells, and halts the progression from severe insulitis to diabetes. We conclude that a vidity maturation of pathogenic T-cell populations may be the key event in the progression of benign inflammation to overt disease in autoimmunity.