Reversing senescence and exhaustion signalling pathways in primary human T lymphocytes during ageing

免疫系统的效力不应被低估。没有有效的免疫系统，我们的身体几天内就会变成腐烂的尸体。然而，这种对入侵微生物的强大防御必须得到有效控制，因为如果我们的免疫系统与我们自己作对，将会有可怕的后果。有两个控制免疫的过程，第一个是称为衰竭的过程，在这个过程中，被称为T淋巴细胞的白细胞过度激活导致其功能活动的丧失。这是通过与T细胞表面的表面蛋白结合来实现的，这种结合可以抑制毒素的产生，从而正确地杀死微生物并防止它们的增殖。因此，衰竭是通过细胞表面抑制受体信号调节的。其次，T淋巴细胞的反复刺激导致其复制能力的丧失，这是由于染色体末端由DNA组成的特殊结构的丧失，这些结构被称为端粒。端粒的过度丢失启动了信号通路，这种信号通路可以感知DNA损伤，从而关闭细胞增殖的能力。这个过程被称为衰老，与衰竭不同，它是由细胞核中受损DNA的信号启动的。随着年龄的增长（70岁左右），我们变得更容易受到感染，即使是那些我们年轻时免疫的感染。这表明免疫系统变得过于脆弱，无法完全有效地防止微生物对我们身体的终身攻击。然而，从老年人身上分离出的T淋巴细胞（白细胞）功能失调的原因尚不清楚。众所周知，来自老年人的T淋巴细胞具有衰老细胞的特征，但尚不清楚它们是否也可能耗尽。我们最近发现，在年轻人（<40岁）中，我们可以阻断细胞中调节衰老的蛋白质或细胞表面调节衰竭的蛋白质，以增加其功能。关键问题是我们能否通过阻断衰老途径、衰竭途径或两者兼而有之来增强老年人T淋巴细胞的功能。这是一个重要的目标，因为人类的人口结构正在向老年化转变，免疫缺陷导致感染和恶性肿瘤的增加。因此，主要目的是：1)研究老年人T淋巴细胞中衰老和衰竭控制因子的表达。2)确定老年人血液中增加的被称为细胞因子的活性介质是否可以开启衰老或衰竭途径。3)研究我们是否可以使用特定的抑制剂来阻止老年人T细胞的衰老或衰竭，以提高它们的功能和增殖能力（我们最近已经证明，这可以在年轻人身上完成）。4)研究阻断衰老或衰竭信号是否可以增加老年人的T细胞的功能活性，这些T细胞是巨细胞病毒（巨细胞病毒呈现衰老）或水痘带状疱疹病毒（带状疱疹病毒在老年人中发病率增加）的特异性T细胞。所有这些工作都将在白细胞上进行，这些白细胞直接从老年人的血液中获得，因此与增强人类衰老过程中出现的免疫缺陷的能力直接相关。

The potency of the immune system should not be undrestimated. Without effective immunity our bodies would turn into rotting carcasses within a few days. However, such a potent defense against invading microorganisms has to be effectively controlled as there would be dire consequences if our immune systems turns against ourselves. There are two processes that control immunity the first is a process called exhaustion, where the over activation of white blood cells known as T lymphocytes leads to loss of their functional activity. This is achieved through binding of surface proteins on the T cell surface that inhibit the production of toxins that kill microorganisms properly and also prevent their proliferation. Exhaustion is therefore regulated by the signalling through cell surface inhibitory receptors. Secondly, the repeated stimulation of T lymphocytes leads to the loss of their replicative capacity and this is due to the loss of specialized structures at the end of chromosomes that are made of DNA and are known as telomeres. Excessive loss of telomeres initiates signalling pathways that sense DNA damage that turn off the capacity of the cell to proliferate. This process is known as senescence and unlike exhaustion, is initiated by signals from damaged DNA in the nucleus.As we get older (>70 years), we become more susceptible to infections, even those to which we were immune in our youth. This indicates that the immune system becomes too fragile to be fully effective in preventing the lifelong assault on our bodies by micro-organisms. However the reasons why the T lymphocytes (white cells) isolated from old individuals are dysfunctional is not known. It is well recognized that the T lymphocytes from older humans have characteristics of senescent cells however it is not know if they may also be exhausted. We have recently found that in young individuals (<40 years), we can block proteins in the cell that regulate senescence or proteins on the cell surface that regulate exhaustion to increase their function. The key question is whether we can boost the function of T lymphocytes from older humans by blocking senescence pathways, exhaustion pathways or both. This is an important goal given the demographic shift of humans towards an older age with defective immunity that leads to increases of infection and malignancy. The main aims therefore are:1) To investigate the expression of senescence and exhaustion control elements in the T lymphocytes of older humans.2) To determine whether active mediators called cytokines that are increased in the blood of older humans can turn on senescence or exhaustion pathways.3) To investigate if we can block senescence or exhaustion in T cells from older humans using specific inhibitors to boost their function and capacity to proliferate (we have shown recently that this can be done in young subjects).4) To investigate whether blocking senescence or exhaustion signalling can increase the functional activity of T cells of older humans that are specific for cytomegalovirus, that appear senescent, or varicella zoster virus that causes shingles, the incidence of which is increased in older humans.All this work will be performed on leucocytes that are obtained directly from the blood of older humans and therefore has directly relevance for the ability to boost the defective immunity that occurs during ageing in humans.