The Functions of Migrating Dendritic Cells

The intestine has a surface area nearly two hundred times greater than the skin, and is exposed to many pathogenic micro-organisms. It requires an effective immune response to protect it from infections. On the other hand, immune responses must not be made against the harmless bacteria and food proteins that are also present. When they occur, these inappropriate responses have serious consequences, leading to inflammatory bowel diseases or food allergies. To ensure our health, the balance between ?immunity? and ?tolerance? must be maintained.
A critical cell for maintaining this balance is the dendritic cell (DC). DCs migrate continually, in lymph, carrying information about the intestine to the immune cells in the mesenteric lymph nodes (MLN). On reaching the MLN, DCs interact with T lymphocytes. This interaction is thought to control whether immunity or tolerance will occur. Understanding how DCs control these processes is likely to be highly beneficial in the design of oral vaccines or prevention of inflammatory bowel diseases. However, study of migrating DCs has been difficult because they cannot easily be separated from other cells in the MLNs. The only way to collect cells which are certain to be migrating DCs is by surgery, which is used to collect the DC-containing lymph. Previously this surgery has only been possible in large animals.
We have developed humane surgical techniques to collect migrating DCs from mice, and to return them to the MLNs. This will enable us, for the first time, to study these cells and their interactions with T cells, using the sophisticated immunological techniques and resources that are only available in mice. We are currently the only group in the world able to collect migrating DCs from mouse lymph. We believe that the study of these cells will generate important information about how immune responses are controlled.

The intestinal immune system must maintain a delicate balancing act, retaining the ability to respond to invading pathogens while also preventing unwanted responses against harmless commensal organisms and food antigens. Dendritic cells (DCs) continually migrate, via lymph, from the intestine to the mesenteric lymph nodes (MLNs), where they prime T cells and direct their differentiation. They are therefore thought to be central to the control of the balance between tolerance and immunity. Understanding this balance is central to the development of oral vaccines, and therapies to prevent or control both food allergies and inflammatory bowel diseases. Study of the immunology of migrating DCs has been hampered by the fact that they cannot be definitively identified in intestinal tissues or in the MLN; unique markers have not been identified. Their properties have been studied in the lymph of rats and larger animals, but these investigations are limited by a lack of immunological reagents, inbred strains, and transgenic animals.
To investigate how migrating DCs interact with T cells and control the balance between tolerance and immunity, we have applied our knowledge of rat surgery to master mesenteric lymphadenectomy and thoracic duct cannulation techniques in the mouse. We have also adapted a technique for intra-lymphatic injection of cells. We are currently the only group in the world able to collect and purify bona fide migrating intestinal DCs. We will use these techniques to address critical questions about the functions of these cells, their fate in vivo, and their interactions with T cells.