Characterisation and functional analysis of factors that define tissue-resident memory T cells and contribute to their sessile phenotype

定义组织驻留记忆 T 细胞并影响其固着表型的因素的表征和功能分析

• 批准号: 234413080
• 负责人: Dr. Asolina Braun
• 金额: --
• 依托单位: Department of Microbiology and Immunology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234413080?language=en
• 关键词: Characterisation; functional; analysis; factors; define

The adaptive immune response generates antigen-specific lymphocytes which recognise the pathogen and contribute to its clearance. During the subsequent memory phase most antigen-experienced T cells such as central memory and effector memory T cells (Tcm and Tem) re-circulate through the body in search of the pathogen. However, as demonstrated in various infectious models an additional CD8+ memory T cell population looses its migratory capacities and resides at epithelial barriers. These cells have been termed tissue-resident memory T cells (Trm) and have been identified in various organs as CD8+, CD44high, CD103+, CD69+, VLA-1+ lymphocytes. For example, in the murine herpex simplex virus (HSV) skin infection model long-lived Trm persist in the epidermis without re-distributing to other organs. Upon secondary infection with the virus Trm confer additional protection in regions where they are lodged, resulting in rapid pathogen control. As the existence of Trm and their protective function has only been recognised in recent years, many issues remain unresolved. For instance, it is not clear which factors contribute to the Trm formation or the factors that maintain their survival in peripheral tissues. To address these issues, my project will take advantage of the murine HSV infection model to generate Trm. Several candidate genes associated with Trm formation will be identified and then tested in knockout models and others for their role in generating as well as maintaining Trm as a non-migratory memory population. Additionally, microarray analysis of Trm from different tissues will address whether additionally any tissue-specific factors are responsible for the development and retention of Trm in various organs.Due to the fact that Trm express a specific set of markers and are sessile, the emerging consensus is that they form a unique subpopulation distinct from Tcm and Tem. In order to compare the similarities and differences between Trm, Tcm and Tem I will perform microarray analysis of the different populations in the HSV model. Upon identification of genes specifically expressed in Trm, selected candidates will be knocked down in naïve CD8+ T cells using RNAi technology. Subsequently, the contribution of these adoptively transferred T cells to the Trm pool will be tested. Overall, this work aims to elucidate the major determinants which distinguish Trm from other T cell memory populations and contribute to the resident Trm phenotype. The insight gathered throughout this study will enchance our understanding of this novel memory T cell population and will presumably aid in the development of advanced T cell based vaccines.

适应性免疫反应产生抗原特异性淋巴细胞，识别病原体并有助于清除病原体。在随后的记忆阶段，大多数经历过抗原的T细胞，如中央记忆和效应记忆T细胞(Tcm和Tem)，在体内重新循环，寻找病原体。然而，正如在各种感染模型中显示的那样，额外的CD8+记忆性T细胞群失去了迁移能力，停留在上皮屏障上。这些细胞被称为组织驻留记忆T细胞(Trm)，在不同的器官中被鉴定为CD8+、CD44High、CD103+、CD69+、VLA-1+淋巴细胞。例如，在小鼠单纯疱疹病毒(HSV)皮肤感染模型中，长期存活的Trm持续存在于表皮，而不会重新分布到其他器官。在二次感染病毒时，Trm在它们寄生的区域提供额外的保护，从而快速控制病原体。由于TRM的存在及其保护功能直到最近几年才被认识到，许多问题仍然没有解决。例如，目前还不清楚是哪些因素导致了Trm的形成，或者是哪些因素维持了它们在周围组织中的存活。为了解决这些问题，我的项目将利用小鼠HSV感染模型来生成Trm。与Trm形成相关的几个候选基因将被识别，然后在基因敲除模型和其他模型中测试它们在生成和维持Trm作为非迁移性记忆群体中的作用。此外，对不同组织中Trm的微阵列分析将解决是否还有组织特异性因素导致Trm在不同组织中的发展和保留。由于Trm表达一组特定的标志物并具有固位性，新出现的共识是它们形成了不同于中医和Tem的独特亚群。为了比较三者之间的异同，我将对单纯疱疹病毒模型中的不同群体进行基因芯片分析。一旦鉴定出在Trm中特异表达的基因，选定的候选者将使用RNAi技术在幼稚的CD8+T细胞中被击倒。随后，将测试这些过继转移的T细胞对Trm池的贡献。总之，这项工作旨在阐明将Trm与其他T细胞记忆群体区分开来的主要决定因素，并对常驻Trm表型做出贡献。通过这项研究收集的洞察力将加深我们对这种新的记忆T细胞群体的了解，并可能有助于开发先进的基于T细胞的疫苗。

项目成果

Persistence of skin-resident memory T cells within an epidermal niche

• DOI: 10.1073/pnas.1322292111
• 发表时间: 2014-04-08
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Zaid, Ali;Mackay, Laura K.;Mueller, Scott N.
• 通讯作者: Mueller, Scott N.

Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes

Hobit和Blimp1指示淋巴细胞组织驻留的通用转录程序

• DOI: 10.1126/science.aad2035
• 发表时间: 2016-04-22
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Mackay, Laura K.;Minnich, Martina;van Gisbergen, Klaas P. J. M.
• 通讯作者: van Gisbergen, Klaas P. J. M.