Homing of lymphocytes to and their function in the intestinal mucosa
The intestinal mucosa presents an enormous surface area (approx 400 square meters) to the external environment and is the primary site of entry for many viral, parasitic and bacterial pathogens.
The intestinal mucosa has developed a unique set of innate and acquired immune defence mechanisms to combat attack by these microorganisms while at the same time tolerating innocuous foreign antigen found in the food we eat and the normal intestinal bacterial flora.
Acquired immune defence mechanisms include the presence of large numbers of antibody secreting cells and activated T cells that are continually present in the intestinal mucosa. The majority of T cells enter the intestinal mucosa following their activation in lymph nodes and localise diffusely throughout the intestinal lamina propria and the single layered epithelium that separates the host from the contents of the intestinal lumen.
While these T cells play a critical role in intestinal immune defence, dysregulated intestinal T cell responses are thought to underlie the induction and maintenance of chronic Inflammatory Bowel Diseases (IBD) such as Crohn’s disease and Ulcerative Colitis, as well as enteropathies associated with food hypersensitivity such as celiac disease.
This project will determine the mechanisms regulating T cell migration to the intestinal lamina propria and epithelium. It will examine the role of intestinal inflammation in regulating the degree of T cell migration to the intestine, and whether T cells use similar mechanisms to gain entry into the intestine in the setting of inflammation. Finally it shall determine how regulatory and pathogenic T cell populations are generated in the intestinal mucosa and whether these subpopulations of T cells use similar mechanisms to localise to the intestinal mucosa.
Understanding the underlying mechanisms regulating the generation and localisation of regulatory and pathogenic intestinal T cell populations will provide important insights into the development of intestinal immune responses and are likely to lead to the identification of novel targets for the treatment of IBD. In this regard, several therapies aimed at selectively inhibiting T cell entry to the intestinal mucosa are currently in clinical trials for the treatment of IBD and serve as a “proof of principal” for this type of approach.