Effect of age on functional plasticity of CD4+ T cells infiltrating a localized secondary immune response in humans

老龄化伴随着对传染病的明显易感性，这给迅速老龄化的社会造成了严重的生产力损失、不断增加的医疗费用和生命损失。随着年龄的增长，免疫系统的逐渐衰退--免疫衰老--是与年龄相关的这种易感性增加的主要潜在原因。尽管进行了几十年的研究，但在我们对这一过程的根本性质的理解以及我们保护老年人免受传染病侵袭的实际能力方面仍然存在重大差距。我们的身体在受到感染生物的攻击时会产生免疫反应。这一反应的中心参与者是我们的白细胞(白细胞)，它的作用是保护我们免受感染性因素的侵袭。根据它们分泌的分子，已经鉴定出不同的白细胞群体(亚群)，它们在免疫反应中发挥不同的作用。一个单独的白细胞亚群被称为调节细胞，它们的主要作用是控制其他白细胞。人类免疫学研究中固有的主要问题是，通常只研究血液中的白细胞，而且几乎所有的研究都是在体外进行的。我们已经开发并验证了一种新的模型，用于研究人类在体内的记忆T细胞反应。这包括在皮肤中注射Recall抗原，然后对病变进行活检，以进行免疫渗透的组织学分析，或者使用吸泡技术采集浸润性细胞。利用这一模型，我们建议阐明在不同抗原诱导的免疫反应过程中积累在皮肤中的细胞的功能概况，并确定这些白细胞群体在老年人中的行为是否不同。具体地说，我们希望研究调节细胞和其他功能白细胞群体之间的关系，并探索控制它们行为的机制。这些信息可能使我们能够人为地操纵这种平衡。

Aging is accompanied by a marked susceptibility to infectious diseases, which inflict heavy toll upon the rapidly aging society with regard to lost productivity, mounting health costs and loss of life. The progressive decline with age of the immune system - immunosenescence - is the primary underlying cause of the age-related increase in this susceptibility. Despite decades of research, important gaps remain in our understanding of the fundamental nature of the process, as well as in our practical ability to protect older adults against infectious diseases. Our bodies mount immune responses when attacked by infectious organisms. The central participants in this response are our white cells (leucocytes), whose role is to protect us from the infective agents. Based on the molecules they secrete different populations (subsets) of leucocytes have been identified which play different roles during immune responses. A separate subset of leucocytes is known as regulatory cells and their main role is the control of other leucocytes. The major problems that are inherent in the study of human immunology is that generally, only leucocytes from the blood compartment are studied and that virtually all studies are performed in vitro. We have developed and validated a new model for the study of a human memory T cell response in humans in vivo. This involves the injection of a recall antigen in the skin, followed by either the biopsy of the lesion for histological analysis of the immune infiltration, or the harvest of infiltrating cells using suction blister technology. Using this model, we propose to clarify the functional profile of cells that accumulate in the skin during immune responses induced by different antigens and determine whether these leucocyte populations behave differently in the old individuals. Specifically we wish to examine the relationship between regulatory cells and other functional leucocyte populations and explore mechanisms which control their behaviour. This information may enable us to manipulate this balance artificially.