PTBP proteins in T cell activation: Cellular and molecular mechanisms of action

适应性免疫系统由称为T淋巴细胞和B淋巴细胞的细胞组成，已经进化为提供对有害微生物和寄生虫的保护。这些细胞提供了对以前感染的持久记忆，利用它们的功能是有效接种疫苗的关键。T细胞并不都是一样的，可以分为具有专门功能的组或亚组。这些细胞包括称为T滤泡辅助细胞（TFH）的CD 4 + T细胞，其帮助B细胞产生抗体，以及CD 8 + T细胞，其杀死被病毒或其他细菌感染的细胞。T细胞的重要性促使许多研究人员确定控制其发育、存活和功能的基因。控制T细胞命运和功能的一个主要类别的基因编码在基因转录水平上工作的蛋白质，基因被转化为信使RNA的过程。这一控制层的重要性被普遍接受，并通过使用小鼠遗传学的许多研究来证明，这些研究确定了所涉及的关键基因。然而，另一层控制也很重要，这就是基因表达的转录后调控，它可以调节信使RNA停留的时间以及信使RNA将其信息转化为蛋白质的克里思。与转录调控相比，人们对转录后调控如何控制T细胞的发育和功能知之甚少。我们已经发现一类编码RNA结合蛋白的基因在T细胞中发挥重要的转录后作用。目前尚不清楚它们如何影响T细胞的生物学。我们提出的研究是基于未发表的数据，这些数据确定了T细胞正常发育和功能所必需的关键RNA结合蛋白（RBP）。为了发展这一研究领域，我们希望在整个生物体的水平上了解RBPs在T细胞功能中的冗余作用。我们将使用T细胞中的条件基因靶向来研究突变小鼠的表型。这些条件系统将测试在活化T细胞的发育和维持中的作用。我们将使用蛋白质RNA相互作用的测定来鉴定两种小鼠T细胞中RBP的直接结合靶点。我们将研究靶点的调节模式，这项研究旨在了解T细胞功能所必需的新机制，从而对疫苗的成功和自身免疫产生影响-当T细胞对我们自己的组织产生反应时。重要的是，我们希望了解这种新机制如何与我们最了解的机制-信号传导和转录-相互作用。这项工作是阐明T细胞基因调控的新分子机制的关键一步。对这一机制的重要性和细节的理解有可能为免疫调节开辟新的可能性。

The adaptive immune system, which is comprised of cells called T- and B- lymphocytes, has evolved to provide protection against harmful microorganisms and parasites. These cells provide long-lasting memory of previous infections and harnessing their function is key for effective vaccination. T cells are not all the same and can divided into groups, or subsets, which have specialized functions. These include CD4+ T cells called T follicular helper cells (TFH) which help B cells make antibodies and CD8+ T cells that kill cells infected with viruses or other germs.The importance of T cells has prompted many investigators to identify the genes that control their development, survival and function. One major class of genes that control T cell fate and function encode proteins that work at the level of gene transcription, the process by which genes are converted into messenger RNA. The importance of this layer of control is universally accepted and is exemplified by numerous studies using mouse genetics that identify the key genes involved. However, an additional layer of control is also important; this is called post-transcriptional regulation of gene expression and it can regulate how long messenger RNA sticks around for and the tempo at which the messenger RNA converts its message into protein.When compared to transcriptional regulation, little is known about how post-transcriptional regulation controls the development and function of T cells. We have discovered that a class of genes encoding RNA binding proteins carry out important post-transcriptional roles in T cells. What is unknown is how they affect the biology of T cells. Our proposed research is based on unpublished data that identifies key RNA binding proteins (RBP) necessary for the proper development and function of T cells. To develop this research area we wish to understand, at the level of the whole organism, the redundant role of the RBPs in the function of T cells. We will study the phenotype of mutant mice using conditional gene targeting in T cells. These conditional systems will test for roles in development and maintenance of activated T cells. We will identify the directly bound targets of the RBP in both mouse T cells using assays of protein RNA interaction. We will investigate the mode of regulation of the targets.The research is aimed at understanding a new mechanism that is necessary for T cell function and thus has implications for vaccine success and for autoimmunity-when T cells reacts against our own tissues. Importantly, we wish to understand how this novel mechanism interfaces with the mechanisms that we know most about -signaling and transcription.This work is the key step towards elucidating a novel molecular mechanism of gene regulation in T cells. Appreciation of the importance and understanding the details of this mechanism has the potential to open up new possibilities for immunomodulation.