The function of the chemokine receptor D6 on innate-like B cells

Our immune system protects us from infection and underpins the process of vaccination. The principal cells of our immune system are the white blood cells, of which there are many different types, each with specific immunological tasks. White blood cells are not just found in the blood. They can leave the blood to monitor the health status of our tissues. If they detect an infection, they communicate with other white blood cells whose job is to destroy the infectious agent and ensure that the tissue is repaired. Unfortunately, the immune system has a darker side. In many common diseases, including allergy, autoimmunity, heart disease and cancer, white blood cells use their powers to cause, or perpetuate, disease. As immunologists, our ambition is to understand how the immune system works so that we can improve its protective capabilities, and treat the diseases it causes when it goes wrong. Whether the outcome is protective or destructive, the location of white blood cells is of key importance in all immune responses. If these cells are not in a particular place in the body at a particular time then they are unable to adequately protect against infection or contribute to disease. We are interested in understanding how white blood cells are instructed where to go. Years of investigation have revealed the importance of a group of molecules called chemokines in this process. Chemokines are secreted by tissues, or particular parts of tissues, often in response to damage and infection. They stick to special 'receptor' molecules on the surface of white blood cells. These receptors then tell the cells to move towards the source of the chemokine, and instruct them to start behaving in certain ways. In this way, white blood cells are moved around our bodies either to help ensure effective immune protection, or to contribute to the development of disease. Exciting new medicines are under development that are designed to interfere with chemokines and their receptors to help treat these diseases. Recent clinical studies have been very encouraging. However, many questions remain about chemokines and their receptors, and these questions need to be answered if we are to fully understand the roles they play in immunity and disease. We discovered a receptor for chemokines which we called D6. We are now interested in defining its role in immune responses. Recently, we have found that it is present on particular types of white blood cells called innate-like B cells. These cells are of major importance in protection against bacterial infection because they can rapidly make large quantities of antibodies that help eliminate bacteria. Remarkably, they also appear to play a role in heart disease and autoimmunity. This current proposal aims to reveal the function of D6 on these cells and investigate its importance in their ability to move to the correct locations in the body, produce antibodies, and protect against bacterial infection. Drawing on our team's considerable expertise in this area, we anticipate that our study will radically improve our understanding of how chemokines control white blood cells and the immune system. This may have important ramifications for the design of new medicines.

Chemokines, operating through heptahelical chemokine receptors, are multifunctional leukocyte regulators that play critical roles in innate and adaptive immunity. Best-known for their ability to direct leukocyte trafficking, they can also regulate other key aspects of leukocyte function, such as adhesion, activation, and proliferation. Current dogma contends that the chemokine receptor D6 is a non-signalling scavenger of pro-inflammatory CC chemokines that suppresses inflammation. The mechanistic basis for this theory stems primarily from work using D6 transfected cell lines. However, its function on primary cells has not been investigated. We have developed a novel FACS-based assay to identify cells in mice that express D6. Unexpectedly, we have discovered that, unlike other lymphocyte subsets, marginal zone and B1 B cells show robust expression of D6. These readily-accessible cells, collectively termed innate-like B cells, occupy distinct topographical locations, show unique migratory patterns, and execute key roles during homeostasis and infection through rapid antibody production. Remarkably, despite expressing D6, they are poor chemokine scavengers. Instead, we find that D6 appears to play an indispensable cell autonomous role in controlling B1 B cell abundance and trafficking, and their differentiation into antibody-secreting cells. These data challenge the D6 scavenger model and raise important questions about chemokine regulation of innate-like B cells. In this application, we propose to systematically interrogate, at the molecular, cellular and whole animal level, the role of D6 on innate-like B cells to reveal its importance during homeostasis, immune challenge, and bacterial infection. With our collective expertise, we are uniquely placed to successfully undertake this important and timely study which we anticipate will radically transform our understanding of D6 and provide novel insight into the biology of innate-like B cells