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

1型糖尿病(T1D)是由于免疫失调(自身免疫)导致特定的白细胞(β细胞杀伤淋巴细胞)破坏胰腺的胰岛素产生细胞(β细胞)所致。在过去的几年里，在鉴定β细胞蛋白方面取得了相当大的进展，这些蛋白可以被来自糖尿病人和小鼠的抗体和β细胞反应的白细胞识别。然而，被β细胞杀手白细胞(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，我们已经在分子水平上表征了占主导地位的β细胞杀手白细胞的蛋白质靶标。比较幼稚和分化的β细胞杀手白血CD8细胞的反应性的实验发现，相当出人意料的是，激活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，而这些分子变体完全无法对细胞的幼稚(未刺激)前体细胞产生任何反应。我们收集了令人信服的证据，表明控制未激活的和先前激活的淋巴细胞对不同配体的不同反应性的开关映射到一组与淋巴细胞表面的所谓“T细胞抗原受体”密切相关的分子。这项竞争性更新申请的总体目标是准确定义由这些分子产生的生化事件，这些分子是导致这一意外现象的原因。

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.