MicroRNAs in Tissue-resident memory T cells

项目摘要/摘要 适应性免疫系统的一个决定性特征是存在专门的记忆细胞，它们起源于 以应对初次感染，并在后续感染期间提供持久的免疫力。多种类型 记忆T细胞的存在，具有本地化和功能特化的特征模式。组织- 驻留记忆(TRM)T细胞存在于每个成人组织和器官中，提供局部免疫记忆 以及对感染的反应。了解指定TRM细胞的基因调控程序并使 它们的功能专业化是一个主要目标，最近的发现揭示了几个 转录因子在TRM T细胞中发挥重要作用。在这里，我们建议系统地检查 使用人类和小鼠细胞，microRNAs是否有助于TRM细胞基因调控程序。 MicroRNAs(MiRNAs)是一类小分子调控RNAs，代表着一层必不可少的基因附加层 调控，其作用是在转录后抑制靶mRNAs。值得注意的是，大多数人类基因是 由miRNAs调控，绝大多数基因调控途径被认为包含miRNAs。 在免疫系统中，许多关键事件是由miRNAs调节的，然而，还没有研究对此进行研究 TRM细胞背景下的miRNAs。在Aim I中，我们将使用基因组方法来鉴定 与中枢记忆和效应器记忆相比，在人和小鼠的TRM T细胞中优先表达 T细胞，以及定义调节TRM T转录组的miRNAs的计算工具 细胞。在AIM II中，我们将使用小鼠模型从功能上验证特定miRNAs在TRM T细胞中的作用。 完成这些目标将通过生成所有miRNAs及其 靶向不同的人和小鼠TRM细胞群中的信号。这项研究是关键的第一步 了解特定的miRNAs如何通过增加 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.