Mechanisms underlying the antigenic promiscuity of a pathogenic autoreactive CD8+T-cell specificity

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Type 1 diabetes (T1D) results from immune dysregulation (autoimmunity) leading to destruction of the insulin-producing cells of the pancreas (beta cells) by specific white blood cells (beta cell-killer lymphocytes). Considerable progress has been made in the last few years in the characterization of proteins from beta cells that are recognized by antibodies and beta cell-reactive white blood cells from diabetic humans and mice. However, the nature of the proteins that are recognized by beta cell-killer white blood cells (most of which express the marker CD8) have remained a mystery for a long time. With funding from NSERC, we have characterized, at the molecular level, protein targets of a dominant population of beta cell-killer white blood cells. Experiments comparing the responsiveness of naïve versus differentiated beta cell-killer white blood CD8+ cells have revealed, quite unexpectedly, that activated lymphocytes can mount very efficient responses to molecular variants of the cognate protein that are completely unable to elicit any response on the cells' naïve (unstimulated) precursors. We have gathered compelling evidence that the switch that controls the differential responsiveness of non-activated versus previously activated lymphocytes to different ligands maps to a set of molecules closely associated with the so-called "T cell receptor for antigen" on the surface of lymphocytes. The overall objective of this competitive renewal application is to precisely define the biochemical events emanating from these molecules that are responsible for this unexpected phenomenon.