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

寄生蠕虫感染全球超过20亿人，造成巨大的健康和经济负担。该提案关注的寄生虫是蠕虫，它感染了1.2亿人，并能引起象皮病和河盲症等疾病。它们在人体内存活了几十年，它们使用各种技巧来关闭负责杀死感染的人类免疫反应。这是接种疫苗的主要障碍。有趣的是，这种关闭免疫力的能力也提供了有益的机会，因为一些疾病（过敏，自身免疫）是由不必要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力的技巧来治疗过敏和自身免疫。该提案的目的是确定寄生蠕虫在感染期间如何操纵免疫反应。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大的免疫反应，但如果太强，它可能同时造成损害。这意味着免疫系统必须精细地平衡它如何处理感染，做出足以杀死入侵者而不造成伤害的反应。在慢性感染期间，当持续的强烈免疫反应有更大的机会造成损害时，T细胞可以关闭自己并变得功能惰性。我们发现这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，以便我们可以设计能够重新打开T细胞并清除感染的疫苗或疗法。除了感染，无反应的T细胞也是治疗癌症的一个问题，而不能关闭的T细胞会导致过敏和自身免疫性疾病。因此，从这个建议中获得的知识可以应用于癌症，自身免疫和过敏治疗的发展。

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.