Kinetic evolution of a diabetogenic CD8+ T cell response.

Nonobese diabetic (NOD) mice develop overt diabetes following prolonged periods of pancreatic islet inflammation involving both CD4+ and CD8+ T cells. The initiation and progression of autoimmune diabetes require the recruitment of beta cell-reactive CD8+ T cells to the pancreatic lymph nodes, their activation by antigen, and their subsequent migration into pancreatic islets. We and others have shown that a significant fraction of NOD islet-associated CD8+ T cells express highly homologous TCRalpha chains (Valpha17 and Jalpha42 joined by the same N-region sequence) and that they recognize the peptide NRP-A7 in the context of the MHC class I molecule H-2K(d). We have also shown that this T cell subpopulation undergoes a process of "avidity maturation" that is associated with progression of benign insulitis to overt diabetes. This paper will summarize our current understanding of the mechanisms that drive the recruitment and activation of this CD8+ T cell subpopulation.