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

适应性免疫系统由称为T-和B-淋巴细胞的细胞组成，已经进化为提供针对有害微生物和寄生虫的保护。这些细胞提供对以前感染的长期记忆，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，可以分为具有特殊功能的组或亚集。其中包括被称为T滤泡辅助细胞(TFH)的CD4+T细胞，它帮助B细胞产生抗体，以及CD8+T细胞，它杀死感染病毒或其他细菌的细胞。T细胞的重要性促使许多研究人员识别控制其发育、生存和功能的基因。控制T细胞命运和功能的一类主要基因编码的蛋白质在基因转录水平上工作，基因转录是基因转化为信使RNA的过程。这一层控制的重要性被普遍接受，并通过大量利用小鼠遗传学识别相关关键基因的研究得到了例证。然而，另一层控制也很重要；这被称为基因表达的转录后调节，它可以调节信使RNA停留多长时间，以及信使RNA将其信息转化为蛋白质的速度。与转录调节相比，转录后调节如何控制T细胞的发育和功能知之甚少。我们发现，一类编码RNA结合蛋白的基因在T细胞中发挥着重要的转录后作用。目前尚不清楚它们是如何影响T细胞的生物学的。我们提出的研究是基于未发表的数据，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限制性商业惯例在T细胞功能中的多余作用。我们将利用T细胞中的条件基因打靶来研究突变小鼠的表型。这些条件系统将测试在活化T细胞的发展和维持中的作用。我们将通过蛋白质RNA相互作用的分析来确定RBP在两个小鼠T细胞中的直接结合靶点。我们将调查靶标的调节模式。这项研究的目的是了解一种新的机制，这种机制对于T细胞功能是必要的，因此对疫苗的成功和自身免疫具有意义--当T细胞对我们自己的组织发生反应时。重要的是，我们希望了解这种新的机制是如何与我们最了解的机制-信号和转录-相互作用的。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。认识到这一机制的重要性并了解其细节，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.