Cytotoxic T Cell-Mediated Diabetes in RIP-CD80 Transgenic Mice

: Rodent immune‐mediated diabetes model studies have advanced understanding of β cell–specific T cell responses, and the testing of therapeutic approaches. We have used an inducible diabetes model based on rat insulin promotor (RIP)–driven expression of CD80 (B7‐1) on pancreatic β cells. Using these mice, we have established that immunizing with a single autoantigen can promote progressive islet inflammation and eventually T cell–mediated diabetes. We now describe a potent immunization protocol using peptide‐pulsed mature dendritic cells (DCs) to examine peptide epitopes derived from endogenous (preproinsulin) and transgenically expressed β cell antigens, namely lymphocytic choriomeningitis virus glycoprotein (LCMV‐GP). LCMV‐GP epitopes efficiently promote β cell destruction, and the autoantigenic peptide concentration used to load the DCs correlates directly with diabetes onset. The system allowed us to assess cytotoxic T cell (CTL) fine specificity by immunizing with DCs presenting altered peptide ligands (APLs) of the dominant LCMV‐GP epitope, gp33. Finally, using an adoptive transfer system, we tested alternative in vitro T cell activation conditions, including APLs and mitogens, for their impact on T cell effector function and diabetes onset. Our studies revealed a marked discrepancy between (inflammatory) effector functions and diabetes progression, thus emphasizing the importance of structural identity between sensitizing and target epitope and the context of initial T cell activation.