Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes
Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes
复制标题
DOI：
10.2337/db16-1025
复制
发表时间：
2017-03-01
期刊：
影响因子：
7.7
通讯作者：
Nakayama, Maki
中科院分区：
文献类型：
--
作者：
Michels, Aaron W.;Landry, Laurie G.;Nakayama, Maki
1型糖尿病是由胰岛内产生胰岛素的β细胞的慢性自身免疫性破坏引起的。尽管胰岛素是自身免疫性糖尿病动物模型中的关键自身抗原，但由于获得胰腺样品的途径极其有限，对胰岛浸润T细胞的人类抗原靶点知之甚少。在这里，我们表明，胰岛素原肽的目标是胰岛浸润T细胞从1型糖尿病患者。我们使用直接T细胞受体（TCR）测序方法，在没有长期细胞培养的情况下，从三名患有1型糖尿病的年轻器官捐赠者的炎症胰岛中鉴定了数百个T细胞，这些患者的病程较短，具有高风险HLA基因。在测试对糖尿病易感的HLA-DQ和HLA-DR分子呈递的前胰岛素原肽的反应性的85个选择的CD 4 TCR中，一个T细胞识别C肽氨基酸19-35，并且来自不同供体的两个克隆响应胰岛素B链氨基酸9-23（B：9-23），其已知是自身免疫性糖尿病动物模型中的关键自身抗原驱动的疾病进展。这些B：来自胰岛的9-23特异性T细胞对完整的胰岛素原和胰岛有应答，而先前鉴定的来自外周血的B：9-23应答性克隆没有应答，这突出了胰岛素原特异性T细胞在胰岛微环境中的重要性。
Type 1 diabetes results from chronic autoimmune destruction of insulin-producing beta-cells within pancreatic islets. Although insulin is a critical self-antigen in animal models of autoimmune diabetes, due to extremely limited access to pancreas samples, little is known about human antigenic targets for islet-infiltrating T cells. Here we show that proinsulin peptides are targeted by islet-infiltrating T cells from patients with type 1 diabetes. We identified hundreds of T cells from inflamed pancreatic islets of three young organ donors with type 1 diabetes with a short disease duration with high-risk HLA genes using a direct T-cell receptor (TCR) sequencing approach without longterm cell culture. Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and HLA-DR molecules, one T cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B-chain amino acids 9-23 (B:9-23), which are known to be a critical self-antigen-driving disease progress in animal models of autoimmune diabetes. These B: 9-23-specific T cells from islets responded to whole proinsulin and islets, whereas previously identified B:9-23 responsive clones from peripheral blood did not, highlighting the importance of proinsulin-specific T cells in the islet microenvironment.