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.

我们的免疫系统可保护我们免受病原体，细菌和寄生虫等病原体的感染。与任何防御机制一样，不可避免地会造成附带损害的风险。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）在策划免疫反应，杀死感染细胞和维持免疫记忆（疫苗的基础）中起着核心作用。每个发育的T细胞在表面上都有一个独特的受体，可以与病原体的成分结合，从而识别其存在。每个T细胞都表示这种识别的独特，随机生成的特异性。当然，这种受体总是有潜力识别体内不同的器官。为避免对人体器官的明显攻击，在发育过程中消除了具有强大自我反应性的T细胞。但是，一些自反应性T细胞逃脱了这种消除过程，需要检查一下。最近，已经确定了T细胞 /称为调节T细胞（Tregs） /的亚组。这些T细胞具有自反应性，但是它们没有引发免疫反应，而是抑制了潜在的破坏性T细胞的功能。缺乏这种T细胞种群的人死于对体内不同器官的毁灭性攻击。有很大的兴趣了解Tregs的工作方式。特别是，科学家想知道他们是否可以利用Treg的力量来防止自身免疫性疾病，例如关节炎，糖尿病和多发性硬化症。此外，制药公司针对引起自身免疫性疾病的正常T细胞开发药物，希望避免抑制Treg的功能。 PI 3-激酶是将信息从细胞外部传递到细胞核的酶，从而使细胞可以基于环境提示做出决策。当T细胞识别病原体的成分时，PI 3-激酶途径被激活并影响随之而来的免疫反应的类型。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DUG，这是T细胞中表达的PI 3-激酶的类型（但不是由主要器官中的细胞）。我们发现，使用小鼠在T细胞中pi 3-激酶活性在遗传上被阻断，Tregs无法阻止常规T细胞的功能。对于针对P110delta的药物开发，这可能是一个严重的劣势，需要进一步研究。为此，我们打算确定可能受到Treg中缺乏PI 3-激酶活性影响的基因。这将有助于我们更好地理解p110delta抑制如何影响treg，但也可以帮助我们识别Treg功能所需的其他基因；其中大多数目前未知。我们还将研究P110delta在免疫反应过程中如何促进调节性T细胞的发展。迄今为止，大多数实验都是用细胞培养物进行的，不一定完全反映了Treg在自身免疫攻击中的作用。为了进一步检查这一方面，将检查p110delta缺陷treg防止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p110delta缺陷型T细胞的精确缺陷将非常重要。最后，我们将在Tregs中删除P110delta的基因。该实验将确定揭示Treg中的P110DELTA是否对于控制其余的免疫系统是否必不可少。这项研究的好处是，我们将对控制Treg的生命特性的基因和分子有更深入的了解。此外，这项研究将有助于向制药公司告知与针对P110delta的药物相关的优势以及潜在的危险。

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