Regulation of memory T cell lineage differentiation by epigenetic modifications

通过表观遗传修饰调节记忆 T 细胞谱系分化

基本信息

批准号：
7331629
负责人：
JOSHUA J OBAR
金额：
$ 4.68万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7331629
关键词：
Activities of Daily Living Acute Address Adoptive Transfer Affect Antigens Biological Assay CC chemokine receptor 7 CD8B1 gene Cancerous Cell Differentiation process Cell Lineage Cell surface Cells Chromatin Condition Decision Making Development Environment Epigenetic Process Event Frequencies Future Growth High Endothelial Venule Homing Immune Immune response Immunity Immunologic Memory In Vitro Infection Intestines L-Selectin Location Lung Lymphocyte Lymphoid Memory Messenger RNA Modeling Modification Molecular Mus Organ Other Resources Pattern Peripheral Population Process Regulation Reporter Reverse Transcriptase Polymerase Chain Reaction SELL gene Signal Transduction Site Surface System T memory cell T-Lymphocyte Techniques Testing Time Tissues Vaccination Vaccines Virus Diseases antigen resource base chromatin immunoprecipitation in vivo lymph nodes migration pathogen precursor cell prevent protein expression research study response vaccine development

项目摘要

DESCRIPTION (provided by applicant): Immunological memory is the basis for long-lasting protective immunity conferred by vaccination. The cells responsible for providing this protective immunity have different capabilities based on their location in the body, examples include sites exposed to the environment (i.e. lungs & intestine) or immune specific organs (i.e. lymph nodes). In order to construct better vaccines, we are trying to understand what drives the development of these different types of memory cells and how they might be related to one another. The memory T cell population is made up of at least two subsets of memory cells that have distinct homing and functional capacities. CD62L is important for the migration of lymphocytes through the high endothelial venules into lymphoid organs and is an effective marker in distinguishing 'central-memory' cells that reside in lymphoid organs and 'effector-memory' that reside largely in peripheral tissues. By having a diverse memory T cell population the host is provided with multiple layers of protection. How these subsets of memory cells are related to one another is an ongoing debate. We postulate that the two subsets are distinct cell lineages. In this proposal, we will examine whether epigenetic modifications occur within the memory precursor cells, which prevent the interconversion between these two subsets. We will examine whether during the immune response memory precursor cells that have lost CD62L expression have modified their chromatin in such a manner that precludes the re-expression of CD62L. We will also address how competition for resources/antigen affects this process. This proposal will allow us to gain a molecular understanding of memory cell differentiation through the use of chromatin immunoprecipitation assays, real-time RT-PCR and a CD62L reporter mouse system. By understanding how the responding CD8 T cells make their lineage decision we will be able to more effectively target a specific subset of memory cells which in turn may enable us to make more effective vaccines.

描述（由申请人提供）：免疫记忆是疫苗接种赋予的长期保护性免疫的基础。负责提供这种保护性免疫力的细胞根据其在体内的位置具有不同的功能，例如暴露于环境的部位（即肺和肠道）或免疫特异性器官（即淋巴结）。为了构建更好的疫苗，我们正在尝试了解是什么驱动了这些不同类型的记忆细胞的发展以及它们如何相互关系。记忆T细胞种群由至少两个具有独特归纳和功能能力的记忆单元的子集组成。 CD62L对于淋巴细胞通过高内皮细胞迁移到淋巴机构中很重要，并且是区分驻留在淋巴机器人和“效应器 - 内存”中的“中央记忆”细胞的有效标记，这些细胞主要驻留在外围组织中。通过具有多种记忆T细胞种群，宿主获得了多层保护。这些记忆细胞的这些子集彼此之间的关系是一场持续的争论。我们假设这两个子集是不同的细胞谱系。在此提案中，我们将检查表观遗传修饰是否发生在记忆前体细胞中，这阻止了这两个子集之间的互连。我们将研究在免疫反应记忆中失去CD62L表达的前体细胞是否以阻止CD62L重新表达的方式改变了其染色质。我们还将解决资源/抗原竞争如何影响这一过程。该建议将使我们能够通过使用染色质免疫沉淀测定，实时RT-PCR和CD62L报告基因的小鼠系统来获得对记忆细胞分化的分子理解。通过了解响应的CD8 T细胞如何做出谱系决策，我们将能够更有效地针对特定的记忆细胞子集，而记忆细胞的特定子集又可能使我们能够制造出更有效的疫苗。