PI3K signalling in regulatory T cells.

我们的免疫系统保护我们免受病毒、细菌和寄生虫等病原体的感染。与任何防御机制一样，附带损害的风险是不可避免的。免疫系统使用几种不同的策略来限制对宿主的损害。T细胞(一种白细胞)在协调免疫反应、杀死受感染细胞和维持免疫记忆(疫苗的基础)方面发挥着核心作用。每个发育的T细胞表面都有一个独特的受体，可以与病原体的成分结合，从而识别它们的存在。每个T细胞表达一种独特的、随机产生的这种识别的特异性。当然，这种受体总有可能识别体内不同的器官。为了避免对身体器官的公开攻击，在发育过程中消除了具有强烈自我反应性的T细胞。然而，一些具有自我反应性的T细胞逃脱了这个消除过程，需要加以控制。最近，一个T细胞亚群被鉴定出来，称为调节性T细胞(Tregs)/。这些T细胞是自我反应的，但它们不是启动免疫反应，而是抑制潜在破坏性T细胞的功能。缺乏这种T细胞群体的个体会因对身体不同器官的毁灭性攻击而过早死亡。人们非常有兴趣了解更多关于特雷格是如何工作的。特别是，科学家们想知道他们是否可以利用Tregs的力量来预防自身免疫性疾病，如关节炎、糖尿病和多发性硬化症。此外，制药公司开发针对导致自身免疫性疾病的正常T细胞的药物，希望避免抑制Tregs的功能。PI3-激酶是一种酶，它将信息从细胞外传递到细胞核，允许细胞根据环境线索做出决定。当T细胞识别病原体的一种成分时，PI 3-激酶途径被激活，并影响随后的免疫反应类型。通过抑制PI3-激酶，可以避免某些有害的免疫反应。因此，制药公司目前正在开发和测试针对p110β的DUG，这是一种在T细胞(但不是主要器官中的细胞)中表达的PI 3-激酶类型。我们发现，在T细胞中PI-3-激酶活性被基因阻断的小鼠中，Treg不能阻止传统T细胞的功能。这可能是针对p110 Delta的药物开发的一个严重不利因素，需要进一步调查。为此，我们打算确定在Treg中可能受PI 3-激酶活性缺乏影响的基因。这将帮助我们更准确地了解p110 Delta抑制可能如何影响Treg，但也可能帮助我们识别Treg功能所需的其他基因；其中大多数目前尚不清楚。我们还将研究p110 Delta如何在免疫反应期间促进调节性T细胞的发展。到目前为止，大多数实验都是用细胞培养进行的，不一定完全反映Tregs在自身免疫攻击中的作用。为了进一步研究这一方面，我们将研究p110Delta缺陷树突状细胞预防自身免疫性糖尿病的能力。这需要一个更复杂的细胞相互作用网络，在这种情况下绘制p110增量缺陷T细胞的精确缺陷图将是重要的。最后，我们将删除在Tregs中特定的p110 Delta基因。这项实验将明确地揭示特雷格中的p110 Delta是否对保持免疫系统的其余部分是必要的。这项研究的好处是我们将更好地了解控制Tregs救命特性的基因和分子。此外，这项研究将帮助制药公司了解与靶向p110 Delta的药物相关的优势和潜在危险。

Our immune system protects us from infection by pathogens such as viruses, bacteria and parasites. As with any defence mechanism, the risk of collateral damage is unavoidable. The immune system uses several different strategies to limit the damage to the host. T cells (a type of white blood cell) play a central role in orchestrating immune responses, in the killing of infected cells and in the maintenance of immunological memory (the basis for vaccines). Each T cell that develops has a unique receptor on the surface that can bind to components of pathogens and hence recognise their presence. Each T cell expresses a unique, randomly generated specificity for such recognition. There is of course always a potential for such receptors to recognise different organs in the body. To avoid overt attacks on the body's organs, T cells with strong self-reactivity are eliminated during development. However, some self-reactive T cells escape this elimination process and need to be kept in check. Recently, a subgroup of T cells / called regulatory T cells (Tregs) / has been identified. These T cells are self-reactive, but instead of initiating immune responses, they suppress the function of potentially destructive T cells. Individuals who lack this population of T cells die young from a devastating attack on different organs in the body. There is great interest in learning more about how the Tregs work. In particular, scientists want to know if they can harness the power of Tregs to protect against autoimmune diseases such as arthritis, diabetes and multiple sclerosis. In addition, pharmaceutical companies developing drugs against normal T cells that cause autoimmune diseases, want to avoid inhibiting the function of Tregs. PI 3-kinases are enzymes that relay information from outside the cell to the cell nucleus, allowing the cell to make decisions based on environmental cues. When a T cell recognises a component of a pathogen, the PI 3-kinase pathway is activated and influences the type of immune response that ensues. By inhibiting PI 3-kinases, certain harmful immune responses may be averted. Pharmaceutical companies are therefore currently developing and testing dugs against p110delta, the type of PI 3-kinase expressed in T cells (but not by cells in the major organs). We have found, using mice in which PI 3-kinase activity in T cells has been blocked genetically, that Tregs are unable to block the function of conventional T cells. This could be a serious disadvantage for the development of drugs against p110delta and needs to be investigated further. To this end, we intend to identify genes that may be affected by the lack of PI 3-kinase activity in Tregs. This will help us better understand precisely how p110delta inhibition may affect Tregs, but may also help us identify other genes that are required for Treg function; most of these are currently unknown. We will also examine how p110delta contributes to the development of regulatory T cells during an immune response. Most of the experiments to date were performed with cell cultures and do not necessarily fully reflect the role of Tregs during an autoimmune attack. To examine this aspect further, the capacity of p110delta-deficient Tregs to protect against autoimmune diabetes will be examined. This requires a more complex network of cellular interactions and it will be important to map the precise defects of p110delta-deficient T cells in this context. Finally, we will delete the gene for p110delta specifically in Tregs. This experiment will reveal definitively whether p110delta in Tregs is essential for keeping the rest of the immune system in check. The benefit of this research is that we will gain a greater understanding of the genes and molecules that control the life-saving properties of Tregs. In addition, this research will help inform pharmaceutical companies about the advantages, as well as potential dangers, associated with drugs that target p110delta.