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

• 批准号: 7460709
• 负责人: JOSHUA J OBAR
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 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/7460709
• 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

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（由申请方提供）：免疫记忆是疫苗接种所赋予的持久保护性免疫的基础。负责提供这种保护性免疫的细胞根据其在体内的位置具有不同的能力，例如暴露于环境（即肺和肠）或免疫特异性器官（即淋巴结）的部位。为了构建更好的疫苗，我们正试图了解是什么驱动了这些不同类型的记忆细胞的发育，以及它们之间的关系。记忆T细胞群由至少两个具有不同归巢和功能能力的记忆细胞亚群组成。CD 62 L对于淋巴细胞通过高内皮微静脉迁移到淋巴器官中是重要的，并且是区分驻留在淋巴器官中的“中央记忆”细胞和主要驻留在外周组织中的“效应记忆”细胞的有效标记物。通过具有多样化的记忆T细胞群体，为宿主提供了多层保护。这些记忆细胞的子集是如何相互关联的，这是一个持续的争论。我们假设这两个亚群是不同的细胞谱系。在这个建议中，我们将研究是否表观遗传修饰发生在记忆前体细胞，这阻止了这两个子集之间的相互转换。我们将研究在免疫应答过程中，失去CD 62 L表达的记忆前体细胞是否以排除CD 62 L再表达的方式修饰了它们的染色质。我们还将讨论资源/抗原的竞争如何影响这一过程。这一建议将使我们能够通过使用染色质免疫沉淀分析，实时RT-PCR和CD 62 L报告小鼠系统获得记忆细胞分化的分子理解。通过了解响应的CD 8 T细胞如何做出谱系决定，我们将能够更有效地靶向特定的记忆细胞亚群，这反过来又使我们能够制造更有效的疫苗。