The role of type 2 innate lymphoid cells in autoimmune islet infiltration and diabetes

2型先天淋巴细胞在自身免疫性胰岛浸润和糖尿病中的作用

• 批准号: MR/S009140/1
• 负责人: Lucy Walker
• 金额: $ 72.44万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS009140%2F1
• 关键词: role; type; innate; lymphoid; cells

Type 1 diabetes is an increasing problem in the UK and worldwide, with rising numbers of people being affected year on year. The underlying problem is that the immune system attacks and destroys the cells that make insulin in the pancreas. We know that a type of immune cell called a T-cell is responsible for driving the process, however it does not work alone: coordinated interaction between a number of different cell types is required. Understanding the contribution of these different cell types to the disease process is vital for us to design ways to interfere with the immune-mediated attack in an informed way.While analysing the immune cells infiltrating the pancreas in autoimmune diabetes, we recently discovered a population that has not been reported here before. These so called "Innate Lymphoid Cells" or ILC are relative newcomers to the field but have generated lots of excitement over the last few years. They are rare cells, but appear capable of profoundly influencing immune responses - i.e. they punch above their weight. It has been shown that they can change the way T-cells behave, instructing them to secrete different products and alter the type of immune response that is occurring. We have very recent data showing that they can alter whether T-cells secrete something called IL-21 which we know is linked to the development of type 1 diabetes. It is therefore possible that ILC play a key role in determining whether a destructive immune response against the pancreas is mounted.At present nothing is known about the role of ILC in type 1 diabetes since the area is completely uninvestigated. Our proposed experiments will define how ILC affect T-cells during the initiation of an immune response in the pancreas, and in turn how the T-cells influence the ILCs themselves. We will use clues from our preliminary data, and the latest discoveries from the ILC field, to ask questions about whether ILC respond to dying pancreas cells or interact with nervous system components. By collaborating with leading experts in ILC biology, we will perform experiments to directly test whether ILC influence diabetes induction or progression. Importantly, some of the treatments being developed for autoimmune diseases like type 1 diabetes are likely to act on ILC as well as T-cells. It is therefore vital to understand whether ILC play a positive or negative role in disease development so that these drugs can be used correctly.Collectively this project will build on exciting new data from our group to define the role of a new player in the immune-mediated attack on the pancreas.

1型糖尿病在英国和全世界都是一个日益严重的问题，受影响的人数逐年增加。根本的问题是免疫系统攻击并破坏胰腺中制造胰岛素的细胞。我们知道一种称为T细胞的免疫细胞负责驱动这一过程，但它并不单独工作：需要许多不同细胞类型之间的协调相互作用。了解这些不同类型的细胞对疾病过程的贡献对于我们设计以知情的方式干扰免疫介导的攻击的方法至关重要。在分析自身免疫性糖尿病中浸润胰腺的免疫细胞时，我们最近发现了一个以前没有报道过的群体。这些所谓的“先天类神经细胞”或ILC是该领域的相对新人，但在过去几年中产生了很多令人兴奋的东西。它们是罕见的细胞，但似乎能够深刻影响免疫反应--即它们的作用超出了它们的重量。研究表明，它们可以改变T细胞的行为方式，指示它们分泌不同的产物，并改变正在发生的免疫反应的类型。我们最近的数据显示，它们可以改变T细胞是否分泌一种称为IL-21的物质，我们知道这种物质与1型糖尿病的发展有关。因此，ILC可能在决定是否对胰腺产生破坏性免疫反应方面发挥关键作用。目前，由于ILC在1型糖尿病中的作用完全未经研究，因此对ILC的作用一无所知。我们提出的实验将确定ILC如何影响T细胞在胰腺中的免疫反应的启动过程中，反过来，T细胞如何影响ILC本身。我们将利用我们的初步数据的线索，以及ILC领域的最新发现，来询问ILC是否对垂死的胰腺细胞做出反应或与神经系统成分相互作用。通过与ILC生物学领域的领先专家合作，我们将进行实验以直接测试ILC是否影响糖尿病的诱导或进展。重要的是，一些正在开发的治疗自身免疫性疾病如1型糖尿病的方法可能会作用于ILC以及T细胞。因此，了解ILC在疾病发展中是否发挥积极或消极作用至关重要，以便正确使用这些药物。总的来说，该项目将建立在我们小组令人兴奋的新数据的基础上，以确定免疫介导的胰腺攻击中新参与者的作用。

项目成果

100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes.

• DOI: 10.1093/immadv/ltab024
• 发表时间: 2021-01
• 期刊: Immunotherapy advances
• 作者: Pearson JA;McKinney EF;Walker LSK
• 通讯作者: Walker LSK

Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes.

• DOI: 10.1038/s41590-020-0744-z
• 发表时间: 2020-10
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Edner NM;Heuts F;Thomas N;Wang CJ;Petersone L;Kenefeck R;Kogimtzis A;Ovcinnikovs V;Ross EM;Ntavli E;Elfaki Y;Eichmann M;Baptista R;Ambery P;Jermutus L;Peakman M;Rosenthal M;Walker LSK
• 通讯作者: Walker LSK