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，这些传染病给迅速老龄化的社会造成了生产力损失、医疗费用增加和生命损失等严重损失。随着年龄的增长，免疫系统的逐渐衰退-免疫衰老-是这种易感性与年龄相关的增加的主要潜在原因。尽管进行了数十年的研究，但在我们对这一过程的基本性质的理解以及我们保护老年人免受传染病侵害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性生物体攻击时会产生免疫反应。这种反应的核心参与者是我们的白色细胞（白细胞），其作用是保护我们免受感染因子的侵害。基于它们分泌的分子，已经鉴定了在免疫应答期间发挥不同作用的不同白细胞群体（亚群）。白细胞的一个单独的子集被称为调节细胞，它们的主要作用是控制其他白细胞。在人类免疫学研究中固有的主要问题是，通常只研究来自血液隔室的白细胞，并且几乎所有研究都在体外进行。我们已经开发并验证了一种新的模型，用于研究人类记忆T细胞在人体内的反应。这涉及在皮肤中注射回忆抗原，然后对病变进行活检以进行免疫浸润的组织学分析，或者使用抽吸泡罩技术收获浸润细胞。使用这个模型，我们建议澄清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。具体来说，我们希望研究调节细胞和其他功能性白细胞群之间的关系，并探索控制其行为的机制。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.