Mechanisms of Th2 cell-intrinsic hypo-responsiveness, and its impact on protective immunity and memory to parasitic helminths

Th2细胞固有低反应机制及其对寄生虫保护性免疫和记忆的影响

• 批准号: MR/K020196/1
• 负责人: Matthew Taylor
• 金额: $ 62万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK020196%2F1
• 关键词: Mechanisms; Th2; cell; intrinsic; hypo

Parasitic worms infect over 2 billion people worldwide resulting in huge health and economic burden. The parasites this proposal focuses on are filarial worms, which infect 120 million people, and can cause diseases such as elephantiasis and river blindness. They survive within humans for decades, and they do this using a variety of tricks to turn off the human immune responses that are responsible for killing infections. This poses a major barrier for vaccinations. Interestingly, this ability to switch off immunity also provides beneficial opportunities as some diseases (allergies, autoimmunity) are caused by unwanted or incorrect immune responses. This means we can harness the tricks parasites use to subdue immunity to treat allergies and autoimmunity. The aim of this proposal is to identify how parasitic worms manipulate immune responses during infection. The central controller of immune responses is the T cell, and this cell-type is responsible for directing how immune responses clear infection. Although a strong immune response is required to kill parasites, if too strong it can cause damage at the same time. This means the immune system must finely balance how it deals with infection, responding just enough to kill the invader without causing injury. During chronic infection, when there is a greater chance of a sustained strong immune response causing damage, T cells can switch themselves off and become functionally inert. We find that this happens to the T cells responsible for killing helminths and as a consequence the parasite is not cleared. We are investigating the mechanisms by which T cells become inert during infection so that we can design vaccines or therapies able to switch T cells back on and clear infection. Alongside infection, unresponsive T cells are also a problem for treating cancers, whilst T cells that fail to switch-off cause allergies and autoimmune diseases. Thus, knowledge from this proposal can be applied to the development of treatments for cancers, autoimmunity, and allergies.

寄生虫感染全球20多亿人，造成巨大的健康和经济负担。这项提案关注的寄生虫是丝虫，它们感染了1.2亿人，可能会导致象皮病和河盲症等疾病。它们在人类体内存活了几十年，它们使用各种技巧来关闭负责杀死感染的人类免疫反应。这对疫苗接种构成了一个主要障碍。有趣的是，这种关闭免疫的能力也提供了有益的机会，因为一些疾病(过敏、自身免疫)是由不想要的或不正确的免疫反应引起的。这意味着我们可以利用寄生虫用来抑制免疫的伎俩来治疗过敏和自身免疫。这项提议的目的是确定寄生蠕虫如何在感染期间操纵免疫反应。免疫反应的中央控制器是T细胞，这种细胞类型负责指导免疫反应如何清除感染。虽然杀死寄生虫需要强烈的免疫反应，但如果太强，可能会同时造成损害。这意味着免疫系统必须微妙地平衡应对感染的方式，做出恰到好处的反应，在不造成伤害的情况下杀死入侵者。在慢性感染期间，当持续的强烈免疫反应造成损害的可能性更大时，T细胞可以关闭自己，变得功能惰性。我们发现，这种情况发生在负责杀死蠕虫的T细胞上，因此寄生虫没有被清除。我们正在研究T细胞在感染过程中变得惰性的机制，以便我们能够设计能够重新启动T细胞并清除感染的疫苗或疗法。除了感染，没有反应的T细胞也是治疗癌症的一个问题，而未能关闭的T细胞会导致过敏和自身免疫性疾病。因此，来自这项建议的知识可以应用于癌症、自身免疫和过敏治疗的开发。

项目成果

Use of the Litomosoides sigmodontis Infection Model of Filariasis to Study Type 2 Immunity.

使用丝虫病 Litomosoides sigmodontis 感染模型研究 2 型免疫。

• DOI: 10.1007/978-1-4939-7896-0_2
• 发表时间: 2018
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Fulton A

Schistosoma mansoni Larvae Do Not Expand or Activate Foxp3+ Regulatory T Cells during Their Migratory Phase.

• DOI: 10.1128/iai.00408-15
• 发表时间: 2015-10
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Redpath SA;van der Werf N;MacDonald AS;Maizels RM;Taylor MD
• 通讯作者: Taylor MD

ICOS controls Foxp3(+) regulatory T-cell expansion, maintenance and IL-10 production during helminth infection.

• DOI: 10.1002/eji.201242794
• 发表时间: 2013-03
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Redpath, Stephen A.;van der Werf, Nienke;Cervera, Ana M.;MacDonald, Andrew S.;Gray, David;Maizels, Rick M.;Taylor, Matthew D.
• 通讯作者: Taylor, Matthew D.

Th2 cell-intrinsic hypo-responsiveness determines susceptibility to helminth infection.

• DOI: 10.1371/journal.ppat.1003215
• 发表时间: 2013-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: van der Werf N;Redpath SA;Azuma M;Yagita H;Taylor MD
• 通讯作者: Taylor MD

Inherent maternal type 2 immunity: Consequences for maternal and offspring health.

• DOI: 10.1016/j.smim.2021.101527
• 发表时间: 2021-11
• 期刊: Seminars in immunology
• 影响因子: 7.8
• 作者: M. Taylor;Jamie Pillaye;W. Horsnell