Characterization of CD8 T cells in human Type 1 Diabetes

人类 1 型糖尿病中 CD8 T 细胞的特征

• 批准号: 329313839
• 负责人: Dr. Christine Bender
• 金额: --
• 依托单位: La Jolla Institute for Immunology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/329313839?language=en
• 关键词: Characterization; CD8; cells; human; Type

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.

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。可以使用原位四聚体染色在人类糖尿病供体的胰岛中鉴定这些细胞。 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的重要潜在驱动因素。然而，人们对 T1D 人类胰腺细胞的特异性和表型/功能知之甚少。此外，他们最近发现，在人类 T1D 的外分泌组织中可以发现大量 CD8 T 细胞。这种情况的发生与胰岛素的存在无关，并且支持这样的观点：在某些情况下，外分泌胰腺中的非特异性炎症环境可能导致 T1D 发病机制。最后，病毒长期以来一直被认为是 T1D 发展的关键因素，但仍然缺乏在糖尿病发生期间病毒在胰腺中存在的明确证据。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 细胞库的特征，并了解它们的特异性和表型如何随着疾病进展而演变。目标 1：确定人类 T1D 外分泌组织中 CD8 T 细胞的自身抗原特异性和表型，并将其与胰岛内发现的细胞进行比较。目标是系统地表征胰腺中浸润性自身反应性 CD8 T 细胞群。我将通过共染色感兴趣的表型标记物和细胞因子来评估自身反应性 CD8 T 细胞的数量和激活状态。我将研究病程较短和较长的捐献者以及糖尿病前期捐献者，以确定特异性如何随着时间和病程的变化而变化。目标 2：研究病毒感染与人类 T1D 的关联：目标是评估与人类胰腺的组织病理学和病毒存在的标志性迹象相关的病毒特异性 CD8 T 细胞的存在和频率。2.1：识别识别胰腺中病毒抗原的人类 CD8 T 细胞：在这个目标中，我将识别对常见病毒（例如巨细胞病毒或巨细胞病毒）具有特异性的 CD8 T 细胞。 Epstein-Barr 病毒和肠道病毒并比较它们的频率。病毒特异性 T 细胞在疾病不同阶段的存在可能表明与疾病的发生和/或进展可能存在相关性。 2.2：将病毒特异性 T 细胞的存在与人类 T1D 中病毒特征的检测联系起来：在这个子目标中，我将研究抗病毒细胞在具有病理变化的胰岛中是否以增加的频率存在。这项研究将是第一个系统地表征人类胰腺中自身反应性 CD8 T 细胞的研究。我们的工作将提供有关人类 T1D 发病机制的重要信息，并可能为新疗法带来更多机会。