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

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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.