Understanding the regulation of thymus function to control self-tolerant T-cell production

所有脊椎动物的免疫系统都是由一系列细胞和器官组成的。在组成免疫系统的细胞中，T细胞是一个重要的组成部分，因为它们实现了免疫反应的多个基本方面。它们有能力在感染过程中识别和破坏入侵的生物体，如病毒和细菌。T细胞也直接帮助其他重要的免疫细胞类型，如制造抗体的B细胞。T细胞识别病原体的功能能力是疫苗接种成功的基础。在免疫器官（称为淋巴组织）中，胸腺是免疫系统的一个重要的、非冗余的组成部分。它是身体中唯一支持T细胞发育的地方。它也是人体最后一个被赋予功能的部分，其免疫学重要性于1961年被发现。胸腺的重要性可以在动物和人类由于发育过程中发生的缺陷而缺席的情况下看到。这导致致命的免疫缺陷，一种缺乏功能齐全的免疫系统的情况。此外，异常的胸腺功能可以导致T细胞的产生，这些T细胞识别并破坏我们自己的身体组织，而不是入侵剂。这是包括糖尿病在内的多种形式的自身免疫性疾病的基础。从我们和其他人的工作中，我们知道胸腺中不同类型的上皮细胞对于识别病原体而不识别我们自己组织的T细胞的形成是必要的。这就是所谓的自我宽容。我们不知道的是，胸腺的上皮细胞是如何能够实施如此复杂的过程的。同样，我们不知道胸腺的上皮细胞是如何发育的，也不知道它们是如何专门支持T细胞发育的。这项研究代表了伯明翰安德森小组25年来的工作计划，其目的是了解胸腺如何独特地专门产生保持我们健康的T细胞。我们将研究胸腺中的上皮细胞如何发育，以及它们如何相互作用并指导T细胞的发育。这项研究很重要，因为胸腺的功能在一系列临床环境中至关重要，不仅是自身免疫和免疫缺陷。例如，随着我们年龄的增长，功能性胸腺组织会丢失，胸腺在生命早期达到最大尺寸，然后逐渐下降。这意味着老年人的胸腺在产生新的T细胞方面非常低效。此外，正常胸腺功能的丧失阻碍了骨髓移植治疗某些癌症的成功。因此，尽管移植的骨髓提供了新的免疫系统的种子，但胸腺功能的恶化意味着无法有效地处理移植物以产生新的T细胞。如果我们能够了解胸腺如何正常发育和功能，我们可能能够产生恢复胸腺功能和T细胞发育的方法，从而改善免疫反应并提高老年人的疫苗接种成功率，并使癌症治疗后更有效地产生必需的T细胞。

The immune system of all vertebrate animals is made up of a series of cells and organs. Of the cells that make up the immune system, T-cells are an essential component as they fulfil multiple essential aspects of an immune response. They have the ability to recognise and destroy invading organisms such as viruses and bacteria during infection. T-cells also directly help other important immune cell types, such as B-cells that make antibodies. The functional ability of T-cells to recognise pathogens underpins the success of vaccination. Of the immune organs, termed lymphoid tissues, the thymus represents an essential, non-redundant component of the immune system. It is the only place in the body that supports the development of T-cells. It is also the last part of the body to be given a function, with its immunological importance being discovered in 1961. The importance of the thymus can be seen in situations where it is absent from animals and man, due to defects that occurred during development. This leads to fatal immunodeficiency, a situation where a fully functional immune system is absent. Additionally, abnormal thymus function can lead to the generation of T-cells that recognise and destroy our own body tissues, instead of invading agents. This is the basis of multiple forms of autoimmune diseases including diabetes. From our work and that of others, we know that distinct types of epithelial cells in the thymus are necessary for the formation of T-cells that recognise pathogens and do not recognise our own tissues. This is called self-tolerance. What we don't know is how the epithelial cells of the thymus are able to impose such a complex process. Equally, we don't know how the epithelial cells of the thymus develop, and how they become specialised to support a full programme of T-cell development. The aim of this research, which represents a programme of work of over 25 years carried out by the Anderson group in Birmingham, is to understand how the thymus is uniquely specialised to produce T-cells that keep us healthy. We will examine how the epithelial cells in thymus develop, and how they interact and guide the development of T-cells. This research is important as the function of the thymus is critically important in a range of clinical settings, not only autoimmunity and immunodeficiency. For example, functional thymus tissue is lost as we grow older, with the thymus reaching maximal size early in life, followed by a progressive decline. This means that the thymus of elderly people is very inefficient at producing new T-cells. In addition, the loss of normal thymus function impedes the success of bone marrow transplantation for the treatment of certain cancers. So, although transplanted bone marrow provides the seed of a new immune system, deteriorating thymus function means there is an inability to efficiently process the transplant to produce new T-cells. If we can understand how the thymus develops and functions normally, we may be able to generate approaches to restore thymus function and T-cell development that improve immune responses and enhance vaccination success in the elderly, and enable more effective production of essential T-cells following the treatment of cancer.