Induced pancreatic inflammation is controlled in mice by extrapancreatic insulin expression and CD8 T cells limiting autoimmune attack (BA14P.209)

Abstract

Abstract Type 1 diabetes can be induced by virus expressing SIINFEKL in Rat Isulin Promoter (RIP)-OVA transgenic mice harboring adoptively transferred naïve antigen-specific OT1 T cells. By titrating the number of transferred OT-1 cells, disease outcome can be manipulated. Mice receiving high numbers of OT-1 cells develop autoimmunity and rapidly succumb to disease. Mice receiving limiting numbers develop hyperglycemia transiently and then over 10 days recover glucose homeostasis. Recovered mice exhibit restored normal resting blood sugar levels and are able to regulate glucose during a stress test. Histological examination of the pancreas showed extensive pancreatic destruction with no or very few remaining insulin-positive islets. Using RIP-OVA mice expressing luciferase under the mouse insulin promoter, pancreatic insulin promoter activity was extinguished, while liver expression increased in recovered animals, suggesting an ectopic source of insulin can support glucose homeostasis in mice with extensively damaged islets. Pancreatic infiltrates during peak inflammation contained host-derived CD8 T cells in addition to the infiltrating OT-1 cells. These host CD8 T cells were absent in CD8 deficient RIP-OVA mice, and diabetes occurred with fewer transferred OT-1 cells and was quickly fatal. Reconstitution of the CD8 compartment protected these animals. These findings indicate the importance of host CD8 T cells in limiting autoreactive T cell-mediated destruction of islets.