Dissecting the molecular mechanisms of PI3K in Extra-Follicular Helper and Regulatory T cell differentiation

一个多世纪以来，人们一直认为感染引起抗体反应的机制具有根本性的重要性。我们现在了解到，许多不同类型的细胞相互协作，以形成抗体，并产生免疫记忆--疫苗有效的基础原理。抗体是由称为抗体分泌浆细胞(ASC)的特殊细胞产生的。这些细胞是从称为B淋巴细胞的细胞发展而来的。发育过程由另一种称为辅助T淋巴细胞的细胞促进，而被第三种称为调节性T淋巴细胞的细胞抑制。在沙门氏菌感染期间，ASC会产生强大的抗体反应，辅助T细胞和调节性T细胞在这方面都发挥着作用。辅助性和调节性T细胞反应的频率和效力是由T细胞表面受体产生的信号通路介导的。这个信号传递过程的一个组成部分是一种名为磷脂酰肌醇3-激酶(PI3K)的酶--特别是编码p110d亚单位的基因。这种酶控制着细胞中的许多过程，并作为协调器来调节细胞的数量和效力。我们的研究项目的目标是了解PI3K实现这一目标的基本分子机制。我们已经确定了PI3K抑制的一个促进辅助性T细胞功能的途径，我们想要更详细地了解PI3K作用于该途径的哪些组成部分。我们已经确定了更多的分子，这些分子是PI3K调节的良好候选者，我们想要确认这些分子，并确定它们是否以及如何与我们认为重要的途径结合。最后，我们想测试一种新的分子机制，我们认为这对辅助T细胞的良好功能将是重要的。为了做到这一点，我们将使用从未用于T淋巴细胞的新技术。这项新技术将提供对DNA中编码的基因如何转化为使细胞工作的蛋白质的洞察力。

The mechanisms by which infections elicit antibody responses have been recognised as one of fundamental importance for over a century. We now understand that many different cell types collaborate to enable antibody formation, and for the generation of immunological memory - the underpinning principle of vaccine efficacy.Antibodies are produced by specialised cells called antibody secreting plasma cells (ASC). These develop from cells called B lymphocytes. The process of development is promoted by another type of cell called the helper T lymphocyte and inhibited by a third type of cell called the regulatory T lymphocyte. Other cell types are involved, but the balance between the helper and the regulatory T cell is the ultimate determinant of the response.During infection by salmonella bacteria a robust antibody response is generated by ASC and both helper and regulatory T cells play a role here. The frequency and potency of the helper and regulatory T cells response is mediated by signalling pathways that arise from receptors on the T lymphocyte cell surface. One component of this signalling process is an enzyme called phosphatidylinositol 3-kinase (PI3K)-specifically the gene encoding the p110d subunit. This enzyme controls many processes in cells and acts a coordinator to regulate cell number and potency. The goal of our research project is to understand the basic molecular mechanisms by which PI3K achieves this. We have already identified one pathway that PI3K inhibits in order to promote helper T cell function and we want to gain a more detailed understanding of which components of this pathway PI3K acts on. We have identified additional molecules that are good candidates for regulation by PI3K and we want to confirm these and identify if and how they join up with the pathways we think are important. Finally, we want to test a new molecular mechanism that we believe will be important for helper T cells to function well. To do this we will employ novel technology that has never been used on T lymphocytes. This new technology will provide insight into how genes that are encoded in the DNA are converted into proteins that makes cells work.