Mechanism for CD8+ T cell recognition and removal of senescent tissue cells during ageing

流行的观点是，在人的一生中，微生物对免疫系统的反复刺激会耗尽特定类型的白细胞，使其衰老。这可能就是免疫力随着年龄增长而下降的原因。因此，令人惊讶的是，这些老细胞非但没有衰老，反而变得非常善于以一种混杂的方式对感染做出反应，而不是使用它们通常非常特定的微生物识别装置。因此，在衰老过程中，白细胞适应更广泛地对微生物作出反应，而不是完全失去其功能。我们的初步实验确定了一组被称为sestrins的蛋白质，它们调节着这种功能的交换。我们将首先进一步探索促凝素的作用，以了解它们可以调节的人类白细胞功能变化的广度。我们还将通过研究不表达该受体的老年转基因小鼠的白细胞来补充这些研究。衰老过程中老组织的积累会降低器官的功能。在老鼠身上进行的令人兴奋的新研究表明，去除这些老组织细胞可以改善许多不同器官的功能，使老鼠的行为更像年轻的动物。因此，清除组织中的旧免疫细胞可能是恢复器官功能的一种策略，从而在衰老过程中增加幸福感。白细胞可以直接识别和消除组织中的衰老细胞，利用这种相互作用可以改善与年龄相关的器官功能障碍。老年人的白细胞具有更混杂的免疫活性，也能识别和清除老化的组织细胞。因此，调节这种活性获得的甾体蛋白酶可能间接参与体内老细胞的清除。我们将进一步探索白细胞和老组织细胞之间的相互作用，以确定它们可能相互作用的新途径。一个悬而未决的问题是，如果免疫系统能够识别并清除衰老的组织细胞，为什么它们还会在老年人的器官中堆积？我们认为老的组织细胞可以躲避试图杀死它们的白细胞。这种逃避策略涉及器官衰老细胞上抑制受体的诱导。我们已经确定了一种这样的抑制受体，HLA-E，我们现在将调查是否其他也参与其中。了解这种逃避机制的本质可能会导致发现新的方法，使免疫系统更有效地清除衰老细胞，改善老年人的器官功能，从而增加健康和福祉。最后一个问题是，白细胞和老组织细胞之间的相互作用是否发生在现实生活中，而不仅仅是在试管中。我们已经开发了研究人体皮肤免疫力的方法。我们从年轻人和老年人身上取小块皮肤样本，观察同一组织样本中免疫细胞和非免疫细胞的多个不同群体。我们还将向皮肤注射免疫刺激，并研究免疫反应开始后不同时间不同细胞类型之间的多种相互作用。我们将确定不同类型的相互作用之间的免疫细胞和衰老组织细胞在年轻和老年受试者的皮肤。这将为在免疫反应过程中，凝素和NK受体如何在T细胞上发育提供路线图，并有可能确定皮肤中哪些细胞相互作用可以在衰老过程中增强免疫力。

The prevailing view is that the repeated stimulation of the immune system by microbes throughout life exhausts and ages particular types of white blood cells. This may be why immunity decreases during ageing. It was therefore surprising to note that instead of being decrepit, these old cells actually become very good at responding to infections in a promiscuous fashion and not by using their usually very specific microbe recognition apparatus. Therefore, during ageing, white blood cells adapt to respond more broadly to microbes rather than lose their function totally. Our preliminary experiments identify a group of proteins known as sestrins that regulate this exchange of functions. We will first explore the roles of the sestrins further, to understand the breadth of functional changes in human white blood cells that they can regulate. We will also complement these studies by studying white blood cells for old genetically altered mice that do not express the sestrins. The accumulation of old tissue during ageing reduces organ function. Exciting new studies in the mouse have shown that the removal of these old tissue cells improves the function of many different organs and the mouse behaves more like a young animal. Therefore, the removal of old immune cells in tissues may be a strategy for rejuvenation of organ function leading to increased well-being during ageing. White blood cells can directly recognize and eliminate old cells in tissues and exploiting this interaction may improve age-associated organ dysfunction. White blood cells that have more promiscuous immune activity in older people can also recognise and clear old tissue cells. Therefore, the sestrins, that regulate the acquisition of this activity, may be indirectly involved in the removal of old cells in the body. We will explore further the interactions between white blood cells and old tissue cells to identify new ways by which they may interact together. One unanswered question is why do old tissue cells accumulate in organs of aged people if the immune system can recognize and clear them? We think that old tissue cells can hide from white blood cells that are looking to kill them. This evasion strategy involves the induction of inhibitory receptors on the senescent cells in organs. We have identified one such inhibitory receptor, HLA-E and we will now investigate if others are also involved. Understanding the nature of this evasion mechanism could lead to the identification of new ways to enable the immune system to work more efficiently to clear senescent cells and improve organ function in older humans that would lead to an increase in health and well-being.The final question is whether interactions between white blood cells and old tissue cells happen in real life and not just in a test tube. We have developed methods for investigating immunity in human skin. We take small skin samples from young and old individuals and look at the multiple different populations of immune and non-immune cells in the same tissue sample. We will also inject the skin with an immune stimulus and investigate the multitude of interactions between different cell types at different times after the initiation of the immune response. We will identify the different types of interaction between immune cell and senescent tissue cells in the skin of young and old subjects. This will provide a roadmap to how sestrins and NK receptors develop on T cells during an immune response and potentially identify which cellular interactions in the skin can be targeted to boost immunity during ageing.