Cortical Thymic Epithelium: Defining Developmental Pathways and Specialization for Positive Selection

皮质胸腺上皮：定义正选择的发育途径和专业化

• 批准号: G1001055/1
• 负责人: William Jenkinson
• 金额: $ 61.36万
• 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: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1001055%2F1
• 关键词: Cortical; Thymic; Epithelium; Defining; Developmental

T-cells are key players in cell-mediated immune protection of the body, providing a highly efficient defense against viral and bacterial infection. The thymus represents the primary organ supporting the continuous development of new T-cells throughout an individual?s lifetime. T-cells recognize bacteria and viruses through specialized receptors on the cell surface, termed T-cell receptors (TCR). Each T-cell produced bears a receptor of a single specificity. Continuous generation of T-cells occurs throughout life. This process ensures that T-cells exhausted in the periphery during immune responses are replaced and that enough T-cells of sufficient receptor diversity are present within the body to protect against the vast range of potential foreign invaders to the body. Importantly, TCRs are generated in a random manner through the random joining of multiple gene segments encoding the T-cell receptor. Such random receptor generation gives rise to a huge array of potential TCR receptor specificities. The downside of such random TCR generation is that numerous T-cells are generated bearing useless non-functioning receptors, whereas others may generate T-cells that may recognize the bodies? own tissues potentially causing autoimmune responses. In order to prevent development of either of these two cell types, interactions of developing T-cells with epithelial cells of the thymus delete useless and auto-reactive T cells and provide survival signals to self-tolerant T-cells capable of providing efficient immune protection. Thymic epithelial cells (TEC) therefore represent a key cell type involved in the education of developing T-cells, with the number of T-cells produced by the thymus being directly related to the number of TEC capable of providing survival signals supporting T-cell maturation. Importantly, the thymus undergoes a progressive reduction in size with an increase in age, a process termed thymus atrophy. Less thymic epithelial cells persist, leading to a reduced capacity to support T-cell development. This ultimately causes a reduced output of new T-cells. The potential functional results of which means that aged individuals gradually lose the range of T-cell diversity providing immune protection. In turn, this ultimately results in an increased susceptibility to infection with increasing age.It is therefore clear that the size of the thymus and numbers of thymic epithelial cells directly control the rate of T-cell production and therefore efficiency of immune protection. The mechanisms that regulate the expansion and development of thymic epithelial cells remain unclear. The primary focus of this research project is to accurately identify and isolate thymic epithelial progenitor cells and determine their capacity to generate mature, functional thymic tissue capable of supporting efficient T cell development. In addition, this study will also investigate the cellular-machinery that endows thymic epithelium with the highly specialized functional capacity to support the development of diverse, self-tolerant T-cells.

t细胞在细胞介导的机体免疫保护中起着关键作用，为病毒和细菌感染提供了高效的防御。胸腺代表了一个人体内支持新t细胞持续发展的主要器官。年代一生。t细胞通过细胞表面的特殊受体识别细菌和病毒，称为t细胞受体（TCR）。每个产生的t细胞都有一个单一特异性的受体。t细胞在人的一生中不断产生。这一过程确保了在免疫应答过程中耗尽的外周t细胞被替换，并且体内存在足够的受体多样性的t细胞，以防止大量潜在的外来入侵者进入身体。重要的是，tcr是通过编码t细胞受体的多个基因片段的随机连接以随机方式产生的。这种随机受体的产生产生了大量潜在的TCR受体特异性。这种随机生成TCR的缺点是，生成的大量t细胞携带无用的无功能受体，而其他t细胞可能生成可以识别身体的t细胞。自身组织可能引起自身免疫反应为了防止这两种细胞类型中的任何一种的发展，发育中的T细胞与胸腺上皮细胞的相互作用删除了无用的和自身反应性的T细胞，并向能够提供有效免疫保护的自我耐受的T细胞提供生存信号。因此，胸腺上皮细胞（TEC）代表了参与发育中的t细胞教育的关键细胞类型，胸腺产生的t细胞数量与能够提供支持t细胞成熟的存活信号的TEC数量直接相关。重要的是，随着年龄的增长，胸腺会逐渐变小，这一过程被称为胸腺萎缩。胸腺上皮细胞持续减少，导致支持t细胞发育的能力降低。这最终导致新t细胞的产出减少。其潜在的功能结果意味着老年人逐渐失去提供免疫保护的t细胞多样性范围。反过来，这最终导致随着年龄的增长对感染的易感性增加。因此很明显，胸腺的大小和胸腺上皮细胞的数量直接控制t细胞的产生率，从而控制免疫保护的效率。调节胸腺上皮细胞扩张和发育的机制尚不清楚。本研究项目的主要重点是准确鉴定和分离胸腺上皮祖细胞，并确定其产生成熟的功能胸腺组织的能力，这些组织能够支持有效的T细胞发育。此外，本研究还将研究赋予胸腺上皮高度特化功能的细胞机制，以支持多种自我耐受的t细胞的发展。