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

1型糖尿病（T1D）是由免疫失调（自身免疫）引起的，导致特异性白细胞（杀伤细胞）破坏胰腺的胰岛素生成细胞（β细胞）。在过去的几年中，在对来自糖尿病人和小鼠的抗体和β细胞反应性白细胞识别的β细胞蛋白质的表征方面取得了相当大的进展。然而，被β细胞杀手白细胞（其中大多数表达CD8标记物）识别的蛋白质的性质长期以来一直是个谜。在NSERC的资助下，我们在分子水平上描述了β细胞杀手白细胞的显性群体的蛋白质目标。比较naïve与分化的β细胞杀手白细胞CD8+细胞的反应性的实验显示，相当出乎意料的是，活化的淋巴细胞可以对同源蛋白的分子变异产生非常有效的反应，而这些变异完全不能引起细胞naïve（未刺激的）前体的任何反应。我们已经收集到令人信服的证据，表明控制未激活淋巴细胞与先前激活淋巴细胞对不同配体的差异反应性的开关映射到一组与淋巴细胞表面所谓的“T细胞抗原受体”密切相关的分子。这个竞争性更新应用程序的总体目标是精确定义这些分子产生的生化事件，这些分子负责这种意想不到的现象。

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.