Characterization of CD8 T cells in human Type 1 Diabetes

1型糖尿病（T1D）是一种慢性自身免疫性疾病，其特征是产生胰岛素的β细胞的特异性免疫破坏。这些细胞可以用原位四聚体染色在人类糖尿病供体的胰岛中鉴定出来。CD8 T细胞主要浸润含胰岛素的胰岛，表明胰岛素是自身反应性的重要潜在驱动因素。然而，对于T1D患者胰腺中存在的细胞的特异性和表型/功能知之甚少。此外，他们最近表明，CD8 T细胞可以在人类T1D的外分泌组织中大量存在。这种情况独立于胰岛素的存在而发生，并支持了在某些情况下外分泌胰腺的非特异性炎症环境可能有助于T1D发病的观点。最后，长期以来，病毒一直被认为是T1D发展的关键因素，但在糖尿病发生过程中，它们在胰腺中存在的确凿证据仍然缺乏。总体目标是进一步表征外分泌和内分泌组织中自身和病毒特异性CD8 T细胞池，并了解它们的特异性和表型如何随着疾病进展而演变。目的1：确定人类T1D患者外分泌组织中CD8 T细胞的自身抗原特异性和表型，并将其与胰岛内的CD8 T细胞进行比较。目的是系统地表征胰腺浸润性自身反应性CD8 T细胞群。我将通过对表型标记物和感兴趣的细胞因子进行共染色来评估自身反应性CD8 T细胞的数量和激活状态。我将研究短期和长期疾病持续时间的供体以及糖尿病前期供体，以确定特异性如何随时间和疾病持续时间而变化。目标2:研究病毒感染与人类的协会近年来:我们的目标是评估的存在和频率特异性CD8 T细胞与组织病理学的相关病毒presence.2.1的迹象:人类胰腺和标志识别人类CD8 T细胞识别病毒抗原在胰腺:在这个目标我将与特异性识别CD8 T细胞,常见的如巨细胞病毒或病毒巴尔病毒和肠道病毒和比较他们的频率。在疾病的不同阶段存在病毒特异性T细胞可能表明与疾病的发生和/或进展可能相关。2.2：将病毒特异性T细胞的存在与人类T1D中病毒特征的检测相关联：在本课题中，我将研究在病理改变的胰岛中抗病毒细胞是否以增加的频率存在。这项研究将是第一个系统地描述人类胰腺中自身反应性CD8 T细胞的原位特征。我们的工作将为人类T1D的发病机制提供关键信息，并可能为新疗法带来更多机会。

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the specific immune destruction of insulin-producing beta cells. These cells could be identified in islets of human diabetic donors using in situ tetramer staining. CD8 T cells predominantly infiltrate insulin-containing islets, indicating that insulin is an important potential driver of autoreactivity. However, little is known about the specificity and phenotype/function of the cells present in the human pancreas in T1D. In addition, they have recently shown that CD8 T cells can be found in high numbers in the exocrine tissue in human T1D. This occurs independently of insulin presence and supports the idea that a non-specific inflammatory environment in the exocrine pancreas could contribute to T1D pathogenesis in some cases. Finally, viruses have long been considered key players in the development of T1D, but definitive proof for their presence in the pancreas during diabetogenesis is still lacking. The overall objective is to further characterize the pool of self and virus-specific CD8 T cells in the exocrine and endocrine tissue and to understand how their specificities and phenotype evolve with disease progression. Aim 1: To define the auto-antigen specificities and phenotype of CD8 T cells in the exocrine tissue in human T1D and to compare them to those found inside the islets. The goal is to systematically characterize the infiltrating autoreactive CD8 T cell population in the pancreas. I will assess numbers and activation status of autoreactive CD8 T cells by co-staining for phenotypic markers and cytokines of interest. I will study donors with short and long disease duration as well as pre-diabetic donors to determine how the specificities might change over time and with disease duration. Aim 2: To study the association of viral infection and human T1D: The goal is to assess the presence and frequency of virus-specific CD8 T cells in correlation with the histopathology of the human pancreas and hallmark signs of viral presence.2.1: To identify human CD8 T cells recognizing viral antigens in the pancreas: In this aim I will identify CD8 T cells with specificity to common viruses such as cytomegalovirus or Epstein-Barr virus and enteroviruses and compare their frequencies. The presence of virus-specific T cells at different stages of the disease may indicate a possible correlation with disease initiation and/or progression. 2.2: To correlate the presence of virus-specific T cells with the detection of viral signatures in human T1D: In this subaim I will study whether antiviral cells are present at increased frequencies in islets with pathological changes. This study will be the first to systematically characterize autoreactive CD8 T cells in situ in the human pancreas. Our work will provide critical information on the pathogenesis of human T1D and may lead to additional opportunities for novel therapies.