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

随着年龄的增长，我们对感染的易感性逐渐增加，直接对晚年的健康和福祉产生负面影响。目前的预测估计，到2033年，65岁以上的人口比例将占英国人口的25%（来源：英国医学研究理事会）。因此，很明显，解决与年龄有关的感染风险所造成的问题是一个重大的社会经济和健康挑战。免疫系统保护免受细菌和病毒感染的能力是由广泛的免疫细胞类型共同作用提供的。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内发育，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，这意味着每个T细胞都能够识别和攻击有限范围的传染性病原体。为了确保对个体一生中可能遇到的大量细菌和病毒的有效免疫保护，需要各种不同的T细胞来应对这种多样化的感染性挑战。胸腺和T细胞在提供免疫保护中的核心作用被显示胸腺和T细胞发育遗传缺陷的患者的感染的极端风险和高死亡率所突出。在整个生命中，免疫系统中的T细胞通过磨损不断丢失。为了确保维持T细胞多样性和有效的免疫保护，需要从胸腺持续发育和输出新的T细胞，以平衡外周T细胞的这种持续损失。然而，随着年龄的增长，胸腺会逐渐萎缩。胸腺萎缩的特征在于：功能性胸腺组织的丧失、胸腺脂肪沉积的增加以及支持新T细胞发育的相应能力受限。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和对基于疫苗接种的干预的响应能力降低。此外，T细胞发育能力随年龄增长而丧失对接受基于化疗和放疗的治疗的患者在治疗后有效恢复T细胞免疫力的能力产生负面影响。这直接导致了癌症相关治疗和骨髓移植后对感染的高度易感性。胸腺支持T细胞发育的专门能力是由功能独特的胸腺基质细胞提供的，正是这些细胞在年龄相关的胸腺萎缩中丢失。然而，目前尚不清楚哪些信号和分子参与胸腺基质细胞的维持或丧失，以及它们被老年胸腺中的纤维化组织和脂肪细胞（与炎症过程相关的细胞类型）取代。本项目将研究胸腺光敏素β受体（LTbR）在驱动胸腺萎缩中的作用，LTbR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开发医学治疗干预措施的最终长期目标具有重要意义，这些干预措施将对抗胸腺萎缩并改善老年T细胞发育和免疫力。

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.