MicroRNAs in Tissue-resident memory T cells

项目概要/摘要 适应性免疫系统的一个定义特征是存在专门的记忆细胞，其起源于免疫系统。 并在随后感染中提供持久免疫力。多种类型 记忆T细胞的存在，具有定位和功能特化的特征模式。组织- 驻留记忆（TRM）T细胞驻留在每个成人组织和器官中，提供局部免疫记忆 和对感染的反应。了解指定TRM细胞的基因调控程序， 它们的功能专门化是一个主要目标，最近的发现揭示了几个 在TRM T细胞中发挥重要作用的转录因子。在这里，我们建议系统地研究 microRNA是否有助于TRM细胞基因调控程序，使用人类和小鼠细胞。 microRNA（miRNAs）是一类小的调控RNA，代表了基因表达的一个重要的附加层 调节，其作用是在转录后抑制靶mRNA。值得注意的是，大多数人类基因 基因调控通路由miRNA调控，并且据信绝大多数基因调控通路都包含miRNA。 在免疫系统中，许多关键事件都是由miRNAs调控的，然而，还没有研究对其进行研究。 TRM细胞中的miRNAs。在目标I中，我们将使用基因组方法来鉴定miRNAs， 与中枢记忆和效应记忆相比， T细胞和计算工具来定义调节TRM T转录组的miRNA 细胞在目标II中，我们将使用小鼠模型来功能性地验证特定miRNA在TRM T细胞中的作用。 这些目标的完成将通过产生所有miRNA及其表达的综合概况来开辟新的领域。 在不同的人类和小鼠TRM细胞群体中的靶向特征。这项研究是关键的第一步 为了了解特定的miRNAs如何通过增加免疫力来促进更持久的免疫力， TRM细胞的形成和存活。

Project Summary / Abstract A defining feature of the adaptive immune system is the existence of specialized memory cells, which originate in response to a primary infection, and provide durable immunity during subsequent infections. Multiple types of memory T cells exist, with characteristic patterns of localization and functional specialization. Tissue- resident memory (TRM) T cells reside in each adult tissue and organ provide localized immunological memory and response to infection. Understanding the gene regulatory programs that specify TRM cells and enable their functional specialization is a major goal, and recent discoveries have revealed the identities of several transcription factors that play important roles in TRM T cells. Here, we propose to systematically examine whether microRNAs contribute to TRM cell gene regulatory programs, using human and mouse cells. MicroRNAs (miRNAs), a class of small regulatory RNAs, represent an essential additional layer of gene regulation, which act to repress target mRNAs post-transcriptionally. Notably, the majority of human genes are regulated by miRNAs, and the vast majority of gene regulatory pathways are believed to incorporate miRNAs. In the immune system, many critical events are regulated by miRNAs, however, no studies have investigated miRNAs in the context of TRM cells. In Aim I, we will use genomic approaches to identify miRNAs that are preferentially expressed in human and mouse TRM T cells, compared to central memory and effector memory T cells, and computational tools to define the miRNAs that are acting to regulate the transcriptome of TRM T cells. In Aim II, we will use mouse models to functionally validate roles for specific miRNAs in TRM T cells. Completion of these Aims will break new ground by generating comprehensive profiles of all miRNAs and their targeting signatures in diverse human and mouse TRM cell populations. This study is a pivotal first step towards understanding how specific miRNAs can be used to promote more durable immunity by increasing the formation and survival of TRM cells.