Regulation of T cell differentiation by stimulation strength

免疫系统保护身体免受感染。它是由一组专门的细胞组成的，这些细胞以不同的方式对抗感染。CD8T细胞是一种免疫细胞，可以发现并杀死感染病毒的细胞。当T细胞第一次遇到有害的入侵者时，它会被刺激增殖，它的“子代”细胞会进一步专门化，以执行不同的功能。一些细胞与当前的感染作斗争，而另一些细胞则成为“记忆”细胞，在未来防御同样的感染。先前的研究已经表明，在最初的相遇中，T细胞刺激的强度会影响子代T细胞的专门化。关于这种情况是如何发生的，仍有许多问题。在这项提案中，我将通过调查T细胞如何决定它们将产生的特殊反应类型来回答这些问题。为了做到这一点，我将比较强病毒刺激和弱病毒刺激后的T细胞，并使用最先进的技术来检查单个细胞中哪些基因被打开和关闭。我还将研究淋巴结内的运动以及与其他类型的免疫细胞的相互作用如何影响这一过程。最后，我将比较强刺激后发育的子代细胞和弱刺激后发育的子代细胞，并测试它们对抗重复感染的能力。这些数据将揭示T细胞如何控制其反应，以提供针对当前和未来威胁的正确平衡的保护。这项工作将提高对免疫系统的基本过程的理解，并与旨在操纵T细胞反应的疗法的设计有关。例如，持久的T细胞记忆是疫苗接种的重要目标，了解这些反应是如何发展的可能有助于疫苗设计策略。由于该项目将揭示免疫细胞活动的基本特性，它还可能影响其他免疫学领域的工作，包括癌症免疫治疗和自身免疫性疾病研究。

The immune system defends the body against infections. It is made up of a collection of specialised cells that fight infection in different ways. CD8 T cells are a type of immune cell that can find and kill virus-infected cells. When a T cell first encounters a harmful invader, it is stimulated to multiply, and its "daughter" cells specialise further to perform different functions. Some cells fight the current infection, while others become "memory" cells that provide defence against the same infection in the future. Previous research has shown that the strength of T cell stimulation in this initial encounter affects how the daughter T cells specialise. Many questions remain about how this occurs. In this proposal, I will answer these questions by investigating how T cells make decisions about the type of specialised responses they will develop. To do this, I will compare T cells after strong versus weak virus stimulation and use state-of-the-art techniques to examine which genes are turned on and off within individual cells. I will also examine how movement within lymph nodes and interactions with other types of immune cells impact this process. Finally, I will compare daughter cells that developed after strong stimulation versus those that developed after weak stimulation and test how well they fight a repeat infection. These data will reveal how T cells control their responses to provide the right balance of protection against current and future threats.This work will improve understanding of a fundamental process of the immune system and is also relevant for the design of therapies that aim to manipulate T cell responses. For example, long-lasting T cell memory is an important target of vaccination, and understanding how these responses develop may benefit vaccine design strategies. As the project will reveal fundamental properties of immune cell activity, it may also influence work in other fields of immunology including cancer immunotherapy and autoimmune disease research.