PI3K signalling at the immune synapse asymmetric division and immunological memory.

辅助T细胞是免疫应答的主细胞。T细胞负责检测感染因子，无论是细菌、病毒还是寄生虫；它们负责评估这些感染因子可能造成的潜在损害，并在对宿主造成最小损害的同时，发起比例和选择性的免疫反应，以摆脱感染因子。T细胞在与抗原呈递细胞结合时做出这个决定，抗原呈递细胞是专门吞噬外来颗粒，将它们消化成更小的碎片，并将这些碎片呈递给T细胞的细胞。T细胞通过刺激其他细胞的免疫反应来分泌抗体来消除病原体。细胞毒性T细胞的作用是杀死被感染的宿主细胞，从而使体内的病原体丧失能力。这两种细胞类型都将作为本提案的一部分进行研究。辅助T细胞在几个小时内做出决定，在此期间，T细胞通过一种叫做免疫突触的结构与抗原呈递细胞相对应。突触是免疫学家从神经生物学领域偷来的一个术语。神经元通过突触将信号从一个神经传递到另一个神经，这实际上也是免疫细胞所做的。然而，有重要的区别。免疫细胞是高度机动的，通过淋巴结和不同的组织，如皮肤和肠道，可能会发现感染因子。这种持续的运动对T细胞形成稳定的突触施加了额外的限制——有点像跳伞者在自由落体时试图抓住对方的手。p110delta属于磷酸肌肽3-激酶（简称pi3k）酶家族。我们对老鼠进行了基因改造，使p110delta基因不再起作用。来自这类小鼠的T细胞很难与抗原呈递细胞形成结合物。此外，我们有证据表明p110delta缺陷T细胞不能将自身组织成正确的构象，以最大限度地发挥其读取和解释抗原提呈细胞提供的信号的能力。这项拨款的第一个目的是在分子水平上更全面地描述这些缺陷，因为目前还不清楚为什么p110delta对这些功能很重要。接下来，我们将确定这对T细胞对感染因子作出反应的能力到底有多重要。我们还将监测T细胞在感染单核增生李斯特菌后的反应。这种细菌有时存在于未经巴氏消毒的奶制品中，如奶酪，并可能导致人类疾病。我们将观察从感染小鼠身上提取的T细胞是否能与apc进行功能性结合，以及它们是否能做出适当的反应。此外，我们将测试p110δ缺陷T细胞是否可以分裂成这样一种方式，即一个细胞成为效应细胞（注定要短暂地致力于立即消除感染因子），而另一个细胞成为记忆细胞，在背景中等待，准备在再次遇到特定感染因子时提出更直接有效的反应。这一过程是疫苗发挥作用的基础。这些实验将共同研究p110delta（制药行业正在开发的药物靶点）如何影响防止复发性感染的基本免疫反应。

T helper cells are master cells of the immune response. T cells are responsible for detecting infectious agents, be they bacteria, viruses or parasites; they are responsible for assessing the potential damage these infectious agents can cause, and to mount proportional and selective immune response to get rid of the infectious agent while causing minimal damage to the host. The T cells make this decision as they form conjugate with antigen presenting cells - that is cells that are specialised in devouring foreign particles, digesting them in to smaller fragments, and presenting these fragments to T cells. T cells respond by stimulating other cells of the immune response to secrete antibodies that eliminate the pathogen. Cytotoxic T cells act by killing infected host cells, thus incapacitating the pathogen inside. Both these cell types will be investigated as part of this proposal. T helper cell makes their decisions over several hours during which the T cell corresponds with an antigen presenting cell though a structure called the immune synapse. The synapse is a term immunologists have stolen from the field of neurobiology. Neurons transmit signals from one nerve to another through synapses, which in fact is what immune cells do as well. However, there are important differences. Immune cells are highly motile and travel through the lymph nodes and through different tissues, such as the skin and gut where infections agents may be found. This constant movement places additional constraints on T cells to form stable synapses - a bit like parachutists trying to grab each others hands while in freefall. p110delta belongs to a family of enzymes called phosphoinositide 3-kinases (PI3Ks for short). We have engineered mice in which the gene for p110delta is modified such that the enzyme is no longer functional. T cells from such mice are poor at forming conjugates with antigen presenting cells. Moreover, we have evidence that p110delta-deficient T cells fail to organise themselves in the right conformation to maximise their ability to read and interpret the signals provided by the antigen presenting cells. The first purpose of this grant is to more fully characterise these defects at the molecular level as it is at present not obvious why p110delta should be important for these functions. Next, we will determine how important this actually is for the ability of T cells to respond to infectious agents. We will also monitor how T cells respond after infection with a bacterium called Listeria monocytogenes. This bacterium is sometimes found in unpasteurised milk products, such as cheese, and can cause disease in humans. We will observe in T cells taken from infected mice whether they make functional conjugates with APCs and if they are capable of responding appropriately. In addition, we will test if p110delta-deficient T cells can divide in such a way that one cell becomes an effector cell (destined for a short life dedicated to immediate elimination of the infectious agent), whereas the other cell becomes a memory cell that waits in the background and is prepared to raise an even more immediate and effective response should the particular infectious agent be encountered again. This process is the basis for how vaccines work. Together, these experiments will examine how p110delta, a target for drugs being developed by the pharmaceutical industry, affects fundamental immune responses that protect from recurrent infections.