Regulation of memory T cell lineage differentiation by epigenetic modifications

说明(申请人提供)：免疫记忆是通过接种疫苗获得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它们在体内的位置有不同的能力，例如暴露在环境中的部位(即肺和肠)或免疫特定器官(即淋巴结节)。为了构建更好的疫苗，我们正在试图了解是什么推动了这些不同类型的记忆细胞的发展，以及它们可能是如何相互关联的。记忆T细胞群体由至少两个具有不同归巢和功能能力的记忆细胞子集组成。CD62L对淋巴细胞通过高内皮微静脉进入淋巴器官具有重要作用，是区分位于淋巴器官的“中央记忆”细胞和主要位于外周组织的“效应记忆”细胞的有效标记物。通过拥有不同的记忆T细胞群，宿主被提供了多层保护。这些存储单元的子集是如何相互关联的，这是一个正在进行的辩论。我们假设这两个子集是不同的细胞谱系。在这个建议中，我们将检查是否在记忆前体细胞内发生表观遗传修饰，这阻止了这两个子集之间的相互转换。我们将检查在免疫反应记忆中，失去CD62L表达的前体细胞是否以这种方式修改了它们的染色质，从而阻止了CD62L的重新表达。我们还将讨论对资源/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CD62L报告鼠系统来获得对记忆细胞分化的分子理解。通过了解有反应的CD8 T细胞如何作出谱系决定，我们将能够更有效地针对特定的记忆细胞子集，这反过来可能使我们能够制造更有效的疫苗。

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.