Defining the molecular signals that specify Langerhans cell fate in the adult epidermis.

我们的研究提出了一个基本的问题：“免疫细胞的损伤是如何修复的，从而使皮肤能够保护我们免受疾病的侵害？”“皮肤是人体最大的器官，形成了一个物理屏障，保护我们免受伤害和脱水。然而，皮肤也充满了专门感知感染的免疫细胞。因此，我们可以认为皮肤是一个重要的免疫屏障，保护我们免受通过伤口和伤口进入体内的细菌的侵害。一组专门的细胞称为朗格汉斯细胞（LC），在整个皮肤的外层（称为表皮）形成网络。任何通过皮肤进入人体的细菌都必须通过这个网络，LC对于感知这种入侵非常重要。LC属于一组称为巨噬细胞的白色血细胞。然而，在这组LC是特殊的，因为它们在我们出生之前进入表皮，然后作为一个独立的细胞群在我们的整个生命中保持在那里，分裂非常缓慢以维持网络。这与其他地方的巨噬细胞不同，比如肠道，需要不断被称为单核细胞的白色血细胞取代。问题是一些疾病导致LC网络的破坏。最大的问题是，“当出生前最初形成LC网络的细胞不再存在时，这种损伤是如何修复的？"这个问题特别重要，因为LC网络也会随着年龄的增长而崩溃。老年人更容易患皮肤感染和癌症，而且疫苗也不起作用。我们认为，在我们的一生中，对LC网络的不断破坏导致了LC的损失和皮肤免疫屏障的保护不力。我们在实验室开发了一个实验模型，在这个模型中，LC被破坏，我们可以跟踪它们的替代。我们刚刚发表了令人兴奋的新数据，表明这激活了肠道中通常使用的修复过程，单核细胞进入皮肤以取代出生时形成的LC。但是在表皮中，这个过程是非常低效的;尽管事实上有很多单核细胞进入表皮，但只有不到5%的单核细胞会成为适当的长效LC。这意味着所得到的LC网络密度较低。本研究的目的是找出为什么这么少的单核细胞可以成为LC，以及我们是否可以干预这一过程，使LC网络更快地修复。我们将回答两个重要的问题：单核细胞，这是短寿命的细胞，如何在表皮中成为长寿的LC？为什么单核细胞向LC的转化如此低效，我们可以干预以改善这一点吗？我们认为单核细胞需要移动到毛囊周围表皮的特定部位，在那里它们将能够获得它们成为LC所需的信号。对这些位点的竞争阻止了大多数单核细胞访问这些信号，相反，它们死亡。我们的实验室是一个独特的地方来测试这一点，并回答我们的问题，因为我们已经建立了模型，我们可以用来跟踪新的LC的发展。我们将研究进入表皮如何触发指示单核细胞成为LC的重要基因的开启，并将其与显微镜研究相结合，我们可以直接看到单核细胞在皮肤中的位置以及它们可能与哪些其他细胞交谈。通过回答这些问题，并确定限制我们皮肤中LC数量的因素，我们将能够在未来开发出增强这一过程的新方法，以增加LC数量，并在慢性皮肤病患者和老年人中重建皮肤免疫屏障。

Our research asks the basic question "how is damage to immune cells repaired so that the skin can protect us from disease?"The skin is the largest organ in the body and forms a physical barrier that protects us from injury and dehydration. However, the skin is also full of immune cells which are specialised at sensing infection. As such, we can think of the skin as an important immune barrier that protects us from germs that enter the body via cuts and wounds. A specialised group of cells called Langerhans cells (LC) make a network throughout the outer layer of the skin, called the epidermis. Any germ entering the body via the skin will have to pass though this network and LC are really important for sensing this invasion. LC belong to a group of white blood cells called macrophages. However, within this group LC are special because they enter the epidermis before we are born and then remain there for our whole life as a self-contained group of cells that divide very slowly to maintain the network. This is different from macrophages in other places like the gut that need to be constantly replaced by white blood cells called monocytes. The problem is that some diseases lead to the destruction of the LC network. The big question is then, "how is this damage repaired when the cells that originally formed the LC network before birth are no longer around?" This question is particularly important because the LC network also breaks down as we get older. Elderly people are more prone to skin infections and cancer, and also vaccines do not work as well. We think that the constant damage to the LC network over our life-span contributes to this loss of LC and poor protection by the skin immunological barrier.We have developed an experimental model in our laboratory in which LC are destroyed and we can track their replacement. We have just published exciting new data that show that this activates repair processes normally used in the gut and monocytes travel to the skin to replace the LC that were formed at birth. But in the epidermis this process is very inefficient; despite the fact that a lot of monocytes enter the epidermis, less than 5% of them will become proper long-lasting LC. This means that the resulting LC network is less dense. The aim of this study is to work out why so few monocytes can become LC and whether we can interfere with this process so that the LC network is repaired more quickly.We will answer 2 important questions:How do monocytes, which are short-lived cells, become long-lived LC in the epidermis?Why is the transition of monocytes into LC so inefficient, and can we intervene to improve this?We think that monocytes need to travel to specific parts of the epidermis around hair follicles where they will be able to pick up the signals they need to become LC. Competition for these sites is preventing most monocytes from accessing these signals and instead they die. Our lab is in a unique place to test this and answer our questions because we have already set up the models that we can use to track the development of new LC. We will investigate how entry into the epidermis triggers the switching on of important genes that instruct monocytes to become LC, and combine this with microscopy studies where we can directly see where monocytes sit in the skin and which other cells they might be talking to.By answering these questions, and identifying the factors that that limit numbers of LC in our skin, we will be able to develop new ways of enhancing this process in the future to increase LC numbers and re-build the skin immune barrier in people with chronic skin conditions and in older people.