Role of the Lymphotoxin signaling axis in the regulation of thymic microenvironments: Implications for age-associated thymic atrophy.

淋巴毒素信号轴在胸腺微环境调节中的作用：对年龄相关胸腺萎缩的影响。

• 批准号: BB/M006522/1
• 负责人: William Jenkinson
• 金额: $ 59.1万
• 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=BB%2FM006522%2F1
• 关键词: Role; Lymphotoxin; signaling; axis; regulation

Our susceptibility to infection gradually increases with age, directly contributing towards a negative impact upon health and wellbeing in later life. Current predictions estimate that by 2033 the proportion of individuals over the age of 65 will encompass 25% of the UK population (source: Medical Research Council, UK). It is therefore clear that tackling the problem posed by age-associated infection risk presents a major socio-economic and health challenge. The ability of the immune system to protect against bacterial and viral infection is provided by a wide range of immune cell types acting in concert. One critical immune cell type is the T-cell, responsible for directly killing virally infected cells and supporting our ability to mount protective antibody responses. T-cells develop within a highly specialized organ, termed the thymus that lies within the upper chest cavity. Each T-cell formed within the thymus recognizes a limited range of molecules associated with specific bacteria or viruses via a cell surface receptor termed the T-cell receptor (TCR). Importantly, each T-cell produced within the body bears a single TCR specificity, thereby meaning each T-cell is capable of recognizing and attacking a limited range of infectious pathogens. In order to ensure efficient immune protection against the huge range of bacteria and viruses that an individual is likely to encounter throughout their lifetime, a diverse range of different T-cells are required to meet this diverse, infectious challenge. The central role of the thymus and T-cells in providing immune protection is acutely highlighted by the extreme risk of infection and high mortality rates in patients displaying inherited defects in thymus and T-cell development.Throughout life, T-cells within the immune system are continuously lost through attrition. In order to ensure maintenance of T-cell diversity and efficient immune protection, continuous development and output of new T-cells from the thymus is required to counter-balance this ongoing loss of peripheral T-cells. However, as we age, the thymus undergoes a gradual program of atrophy. Thymus atrophy being characterized by: a loss of functional thymus tissue, an increase in thymus fat deposits and a corresponding restricted capacity to support new T-cell development. As a consequence, elderly individuals exhibit restricted T-cell diversity manifesting in an increased susceptibility to infection and a reduced capacity to respond to vaccination based interventions. In addition, the loss of T-cell development capacity with increasing age negatively impacts upon the ability of patients undergoing chemo- and irradiation based therapy to efficiently restore T-cell immunity post-treatment. This directly leads to a window of high susceptibility to infection following cancer-related treatments and bone-marrow transplantation.The specialized capacity of the thymus to support T-cell development is provided by functionally unique thymic stromal cells, and it is these cells that are lost during age-associated thymus atrophy. However, it is unclear which signals and molecules are involved in either maintenance or loss of thymic stromal cells and their replacement by fibrotic tissue and fat cells in the aged thymus, cell types linked to inflammatory processes. This project will investigate the role of the Lymphotoxin-beta receptor (LTbR), a signaling molecule linked to both normal T-cell development and stromal cell function, in driving thymus atrophy. This project will also investigate the consequences of manipulating this pathway upon T-cell development and immune function. Importantly, the identification of novel molecules and their role in regulating thymus atrophy has important implications for the ultimate long-term goal of developing medical therapeutic interventions that will combat thymus atrophy and improve T-cell development and immunity in old age.

随着年龄的增长，我们对感染的易感性逐渐增加，直接导致对以后生活的健康和福祉产生负面影响。目前的预测估计，到2033年，65岁以上个人的比例将占英国人口的25%（资料来源：英国医学研究委员会）。因此，解决与年龄有关的感染风险问题显然是一项重大的社会经济和健康挑战。免疫系统抵御细菌和病毒感染的能力是由广泛的免疫细胞类型协同作用提供的。一种关键的免疫细胞类型是t细胞，负责直接杀死病毒感染的细胞，并支持我们建立保护性抗体反应的能力。t细胞在一个高度特化的器官中发育，称为胸腺，位于上胸腔内。胸腺内形成的每个t细胞通过称为t细胞受体（TCR）的细胞表面受体识别与特定细菌或病毒相关的有限范围的分子。重要的是，体内产生的每个t细胞都具有单一的TCR特异性，因此意味着每个t细胞都能够识别和攻击有限范围的感染性病原体。为了确保有效的免疫保护，防止个体一生中可能遇到的大量细菌和病毒，需要多种不同的t细胞来应对这种多样化的传染性挑战。胸腺和t细胞在提供免疫保护方面的核心作用，在胸腺和t细胞发育中表现出遗传缺陷的患者中，感染的极端风险和高死亡率尤为突出。在人的一生中，免疫系统内的t细胞会因损耗而不断流失。为了确保t细胞多样性的维持和有效的免疫保护，需要胸腺不断发育和输出新的t细胞来平衡周围t细胞的持续损失。然而，随着年龄的增长，胸腺经历了一个逐渐萎缩的过程。胸腺萎缩的特征是：功能胸腺组织的丧失，胸腺脂肪沉积的增加以及相应的支持新t细胞发育的能力受到限制。因此，老年人表现出有限的t细胞多样性，表现为对感染的易感性增加，对基于疫苗接种的干预措施的反应能力下降。此外，随着年龄的增长，t细胞发育能力的丧失会对接受化疗和放疗的患者在治疗后有效恢复t细胞免疫的能力产生负面影响。这直接导致癌症相关治疗和骨髓移植后感染的高易感性窗口。胸腺支持t细胞发育的特殊能力是由功能独特的胸腺基质细胞提供的，而正是这些细胞在与年龄相关的胸腺萎缩过程中丢失。然而，目前尚不清楚哪些信号和分子参与了胸腺基质细胞的维持或丧失，以及它们被纤维化组织和脂肪细胞替代，这些细胞类型与炎症过程有关。该项目将研究淋巴素受体（LTbR）在驱动胸腺萎缩中的作用，这是一种与正常t细胞发育和基质细胞功能相关的信号分子。该项目还将研究操纵这一途径对t细胞发育和免疫功能的影响。重要的是，新分子的鉴定及其在调节胸腺萎缩中的作用对于开发对抗胸腺萎缩和改善老年t细胞发育和免疫的医学治疗干预的最终长期目标具有重要意义。

项目成果

Redefining thymus medulla specialization for central tolerance.

• DOI: 10.1084/jem.20171000
• 发表时间: 2017-11-06
• 期刊: The Journal of experimental medicine
• 作者: Cosway EJ;Lucas B;James KD;Parnell SM;Carvalho-Gaspar M;White AJ;Tumanov AV;Jenkinson WE;Anderson G
• 通讯作者: Anderson G

T-cell egress from the thymus: Should I stay or should I go?

• DOI: 10.1002/jlb.1mr1217-496r
• 发表时间: 2018-08
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: James KD;Jenkinson WE;Anderson G
• 通讯作者: Anderson G

Natural Th17 cells are critically regulated by functional medullary thymic microenvironments.

• DOI: 10.1016/j.jaut.2015.06.008
• 发表时间: 2015-09
• 期刊: Journal of autoimmunity
• 影响因子: 12.8
• 作者: Jenkinson WE;McCarthy NI;Dutton EE;Cowan JE;Parnell SM;White AJ;Anderson G
• 通讯作者: Anderson G

Border control: Anatomical origins of the thymus medulla.

• DOI: 10.1002/eji.201545829
• 发表时间: 2015-08
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Anderson, Graham;Jenkinson, William E.
• 通讯作者: Jenkinson, William E.

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