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Cytotoxic T Cell–Mediated Diabetes in RIP‐CD80 Transgenic Mice
Author(s) -
PECHHOLD KLAUS,
CHAKRABARTY SAGARIKA,
HARLAN DAVID M.
Publication year - 2007
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1394.008
Subject(s) - cytotoxic t cell , epitope , t cell , ctl* , immunology , biology , cd80 , lymphocytic choriomeningitis , adoptive cell transfer , immune system , context (archaeology) , antigen , cd8 , in vitro , cd40 , paleontology , biochemistry
: 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.