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

1型糖尿病（T1D）由免疫失调（自身免疫）引起，导致胰腺的胰岛素产生细胞（β细胞）被特定的白色血细胞（β细胞杀伤淋巴细胞）破坏。在过去几年中，在来自β细胞的蛋白质的表征方面已经取得了相当大的进展，所述蛋白质被来自糖尿病人和小鼠的抗体和β细胞反应性白色血细胞识别。然而，β细胞杀手白色血细胞（其中大多数表达标记CD8）识别的蛋白质的性质长期以来一直是一个谜。在NSERC的资助下，我们在分子水平上表征了β细胞杀伤白色血细胞的主要群体的蛋白质靶点。比较幼稚与分化的β细胞杀伤白色CD8+细胞的反应性的实验非常出乎意料地显示，活化的淋巴细胞可以对同源蛋白的分子变体产生非常有效的反应，这些同源蛋白完全不能对细胞的幼稚（未刺激）前体产生任何反应。我们已经收集了令人信服的证据表明，开关，控制非活化与先前活化的淋巴细胞对不同配体的差异反应映射到一组分子密切相关的所谓的“T细胞抗原受体”的淋巴细胞表面上。 这种竞争性更新应用的总体目标是精确地定义由这些分子产生的导致这种意外现象的生化事件。

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.