At HealthMap we study infectious diseases, but we often overlook the only reason infectious diseases become important: because our immune systems let us down. When working properly, the immune system protects us from most bacteria, fungi and viruses. But sometimes it does not work as well, and we do not always know why. Researchers are just starting to understand how we might be able to boost our immune responses in the places where we commonly face dangerous invaders. Just this week researchers at Brigham and Women’s Hospital in Boston demonstrated that, depending on the context, immune cells in the skin can either generate a potent immune response, or help silence it. (For background, check out the Nobel Prize website’s cute basic and detailed primers on the immune system)
The study (abstract is free, article is behind a paywall) by Thomas Kupper and colleagues demonstrates that certain immune cells only found in the skin, called Langerhan cells (LCs), play a dual role in the immune system, both activating it in moments of danger, and squelching inappropriate responses that occur in the absence of pathogens.
LCs are a special type of dendritic cell. Over the past two decades, researchers have discovered that dendritic cells (DCs) are some of the most important cells in the immune system. These cells can act in different ways: they can gobble up pathogens anywhere in the body and they can signal other cells, located in the lymph nodes, to take action. For example, they may signal cells to produce antibodies, which help neutralize bacteria and fungi, or they may initiate a response more attuned to fight viruses. DCs are so important, in fact, that Ralph Steinman, one of the 2011 Nobel Prize winners in medicine, once called them “nature’s adjuvant” (an adjuvant is anything that stimulates the immune system).
Dr. Kupper studies how LCs are responsible for triggering memory responses against pathogens our bodies have seen before. When our bodies respond to something it has already fought, it attacks more strongly and more quickly than the first time – this is why vaccines work so well.
But Kupper and colleagues’ recent research, published in the journal Immunity, suggests that LCs’ role might be more diverse than “just” activating the immune system’s memory response. Previous dendritic cell research focused primarily on how these cells initiate immune responses in lymph nodes. But since our memory responses need to be quick, their activation is likely happening out where our bodies first encounter these pathogens, like in the skin itself. Since memory responses are so potent, however, researchers like Dr. Kupper are examining how the immune system decides when to attack and when to hold its forces at bay. These two questions have important implications for autoimmunity and vaccines.
Looking for the car keys under the streetlight
The focus on how DCs generate immune responses came about as an accident of scientific methods. Scientists have been looking for immune responses in the places where its easiest to collect immune system cells, much like the man who lost his keys near his car, but is searching for them across the street simply because that is where the streetlight shines. Lymph node cells have been used because lymph nodes are relatively easy to extract and to study. Researchers euthanize a mouse, dissect it, and then extract their lymph nodes from well-known locations. Further, a handful of lymph nodes can provide enough cells to run a study. However, the lymph nodes are rarely where the body first encounters a pathogen. The first encounter is more often in the skin or in our gut.
Collecting immune cells from the skin is far more difficult than collecting them from the lymph nodes. Squeezing enough LCs out of the skin for a study was virtually impossible until Dr. Kupper’s lab developed a new method to extract high numbers of LCs and other immune cells from skin. This allowed them to create a model of how LCs might trigger memory immune responses on site, without migrating to nearby lymph nodes. Dr. Kupper’s studies of LCs give us windows into more common immune reactions than have been previously studied. Now we can look for our car keys where we dropped them, rather than simply where there is the most light.
To do this, the researchers added C. albicans, a common fungus, to a mixture of LCs and memory T cells they extracted from the skin. Since C. albicans is a common pathogen that should initiate an immune response, it was not surprising when they saw that in the presence of this pathogen, LCs initiated a memory immune response in the T cells.
Interestingly, the response depended on the amount of fungus the researchers added. As more fungus was given, the more the memory T cells reacted. Surprisingly, low amounts of fungus triggered the LCs to send signals that kept the immune response under wraps.
Staying calm under pressure
Preventing an immune reaction is an often-overlooked function of the immune system. Learning how the immune system distinguishes between dangerous pathogens and benign bacteria or fungus can help us design vaccines or boost those responses to better fight infections.
This is why Dr. Kupper’s research is important: it makes significant strides in learning more about how the immune system suppresses responses. The research shows that LCs not only activate the immune system, but also play a role in suppressing it. When the researchers cultured LCs with T cells from the skin, the T cells started to grow, even without any pathogen present. This unexpected response suggests that, in the absence of a dangerous pathogen, the LCs were directing the T cells to suppress immune responses. These growing T cells were of a specific regulatory type of cell (known as Treg cells) that are known to suppress immune responses.
While this paper is only one data point in a larger debate about the role of DCs and LCs in initiating and suppressing immune responses, that scientists now have the ability to study immune responses in the skin rather than only in lymph nodes is a key step forward. This research suggests we might be able to design vaccines that, instead of injecting deep into the muscle, can be given by a patch on the skin that activates the immune system via Langerhan cells. It also suggests that scientists may ultimately be able to sway the immune response towards either tolerance of benign bacteria or fungi or the generation of a strong response to specific pathogens. We are still a long way from these advances, but as the Nobel committee showed in 2011, the study of dendritic cells is our best hope for unlocking the secrets of the immune system.