PI3K signalling in regulatory T cells.

调节性 T 细胞中的 PI3K 信号传导。

• 批准号: BB/E009867/1
• 负责人: Klaus Okkenhaug
• 金额: $ 43.83万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE009867%2F1
• 关键词: PI3K; signalling; regulatory; cells.

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.

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 细胞都表达一种独特的、随机生成的这种识别特异性。当然，这些受体总是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，具有强烈自身反应性的T细胞在发育过程中被消除。然而，一些自身反应性 T 细胞逃避了这一消除过程，需要加以控制。最近，一个 T 细胞亚群/称为调节性 T 细胞 (Treg)/已被识别。这些 T 细胞具有自身反应性，但它​​们不会启动免疫反应，而是抑制潜在破坏性 T 细胞的功能。缺乏这种 T 细胞群的个体会因体内不同器官遭受毁灭性攻击而英年早逝。人们对更多地了解 Tregs 的工作原理非常感兴趣。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，制药公司开发针对引起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。 PI 3-激酶是将信息从细胞外传递到细胞核的酶，使细胞能够根据环境线索做出决策。当 T 细胞识别病原体成分​​时，PI 3 激酶途径就会被激活，并影响随后发生的免疫反应类型。通过抑制 PI 3-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 p110delta 的药物，p110delta 是 T 细胞（但不包括主要器官的细胞）表达的 PI 3 激酶类型。我们使用 T 细胞中 PI 3 激酶活性已被基因阻断的小鼠发现，Treg 无法阻断传统 T 细胞的功能。这对于开发针对 p110delta 的药物可能是一个严重的缺点，需要进一步研究。为此，我们打算鉴定可能受 Tregs 中缺乏 PI 3 激酶活性影响的基因。这将帮助我们更好地了解 p110delta 抑制如何影响 Tregs，但也可能帮助我们识别 Treg 功能所需的其他基因；其中大部分目前未知。我们还将研究 p110delta 在免疫反应过程中如何促进调节性 T 细胞的发育。迄今为止，大多数实验都是在细胞培养物中进行的，不一定完全反映 Tregs 在自身免疫攻击期间的作用。为了进一步研究这个方面，将检查 p110delta 缺陷的 Tregs 预防自身免疫性糖尿病的能力。这需要更复杂的细胞相互作用网络，在这种情况下绘制 p110delta 缺陷 T 细胞的精确缺陷图谱非常重要。最后，我们将删除 Tregs 中的 p110delta 基因。该实验将明确揭示 Tregs 中的 p110delta 是否对于控制免疫系统的其余部分至关重要。这项研究的好处是我们将更好地了解控制 Tregs 救生特性的基因和分子。此外，这项研究将有助于制药公司了解与靶向 p110delta 的药物相关的优势和潜在危险。

项目成果

Signaling by the phosphoinositide 3-kinase family in immune cells.

• DOI: 10.1146/annurev-immunol-032712-095946
• 发表时间: 2013
• 期刊: Annual review of immunology
• 影响因子: 29.7
• 作者: Okkenhaug K

IL-21 promotes CD4 T cell responses by phosphatidylinositol 3-kinase-dependent upregulation of CD86 on B cells.

• DOI: 10.4049/jimmunol.1302082
• 发表时间: 2014-03-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Attridge K;Kenefeck R;Wardzinski L;Qureshi OS;Wang CJ;Manzotti C;Okkenhaug K;Walker LS
• 通讯作者: Walker LS