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

了解胸腺功能的调节以控制自我耐受 T 细胞的产生

• 批准号: MR/N000919/1
• 负责人: Graham Anderson
• 金额: $ 193.92万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN000919%2F1
• 关键词: Understanding; regulation; thymus; function; control

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.

所有脊椎动物的免疫系统均由一系列细胞和器官组成。在组成免疫系统的细胞中，T细胞是必不可少的组成部分，因为它们满足了免疫反应的多个基本方面。他们有能力识别和破坏感染过程中病毒和细菌等入侵生物。 T细胞还直接帮助其他重要的免疫细胞类型，例如生成抗体的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，胸腺代表免疫系统中必不可少的非冗余成分。它是体内唯一支持T细胞发展的地方。它也是身体的最后一部分，它在1961年发现了免疫学重要性。在动物和人不存在的情况下，由于在发育过程中发生的缺陷，胸腺的重要性可以看到。这导致致命的免疫缺陷，这种情况是缺乏功能性免疫系统的情况。另外，异常的百里香功能可以导致识别和破坏我们自己身体组织的T细胞的产生，而不是侵入剂。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。从我们的工作和其他工作中，我们知道，胸腺中不同类型的上皮细胞对于识别病原体并且无法识别我们自己的组织的T细胞的形成是必要的。这称为自我耐受。我们不知道的是百里香的上皮细胞如何施加如此复杂的过程。同样，我们不知道胸腺的上皮细胞如何发展，以及它们如何专门支持T细胞开发的完整程序。这项研究的目的代表了伯明翰安德森集团（Anderson Group）进行的25年以上的工作计划，是要了解胸腺如何独特地专门生产使我们健康的T细胞。我们将研究胸腺中的上皮细胞如何发展，以及它们如何相互作用和指导T细胞的发展。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，不仅是自身免疫性和免疫缺陷。例如，随着年龄的增长，功能性胸腺组织会丧失，胸腺在生命的早期就达到了最大大小，随后逐渐下降。这意味着，老年人的胸腺在产生新的T细胞方面非常低效。另外，正常胸腺功能的丧失阻碍了骨髓移植对某些癌症的治疗。因此，尽管移植的骨髓提供了新的免疫系统的种子，但胸骨功能恶化意味着无法有效地处理移植以产生新的T细胞。如果我们能够理解胸腺的正常发展和功能，我们可能能够生成恢复胸腺功能和T细胞发育的方法，从而改善免疫反应并增强老年人的疫苗接种成功，并在治疗癌症治疗后更有效地产生必要的T细胞。

项目成果

Thymic Epithelial Cells

• DOI: 10.1146/annurev-immunol-051116-052320
• 发表时间: 2017-01-01
• 期刊: ANNUAL REVIEW OF IMMUNOLOGY, VOL 35
• 作者: Abramson, Jakub;Anderson, Graham
• 通讯作者: Anderson, Graham

Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK(+) medullary epithelial progenitors.

• DOI: 10.1002/eji.201546253
• 发表时间: 2016-04
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Baik, Song;Sekai, Miho;Hamazaki, Yoko;Jenkinson, William E.;Anderson, Graham
• 通讯作者: Anderson, Graham

Encyclopedia of Immunobiology

免疫生物学百科全书

• DOI: 10.1016/b978-0-12-374279-7.12001-6
• 发表时间: 2016
• 作者: Faulkner C

Medullary Thymic epithelial cell progenitors: hidden in plain sight.

胸腺髓质上皮细胞祖细胞：隐藏在视线中。

• DOI: 10.1038/nri.2017.27
• 发表时间: 2017
• 期刊: Nature reviews. Immunology
• 作者: Anderson G

The thymus and rheumatology: should we care?

• DOI: 10.1097/bor.0000000000000251
• 发表时间: 2016-03
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1
• 作者: Cosway E;Anderson G;Garside P;Prendergast C
• 通讯作者: Prendergast C