Regulation of Intestinal Dendritic Cell Development and Function

The immune system in our intestine faces a formidable challenge, as it has to recognise, attack and destroy potentially harmful infectious agents, without compromising the health of the gut. However, it also has to ensure that it does not mount similar attacks against food or the innocuous bacteria that live in our intestine and which are essential for our health. However these harmless materials are not just ignored, as deliberate and active processes are triggered to make sure that the entire immune system cannot respond. This is called 'tolerance' and most people maintain a healthy balance between immune attack and tolerance. Inappropriate attacks on harmless foods or bacteria in the gut can cause chronic inflammation, such as coeliac disease or Crohn's disease, while ineffective immune responses mean intestinal infections remain major causes of morbidity and mortality worldwide. By understanding how the intestinal immune system decides how to react, we hope to find new ways of boosting responses when vaccinating against intestinal infections, and to develop new medicines for treating inflammatory bowel diseases.
Cells called dendritic cells are crucial in all aspects of the immune response, as they decide whether active immunity or tolerance occurs. They do this by interpreting signals from the environment and instructing T lymphocytes how to react to the different foreign materials which enter the body. As there are several different kinds of dendritic cells, each with separate roles, it is thought that this could be exploited for deliberately manipulating immune responses in disease or for vaccines. The intestine contains many dendritic cells, where they are known to be important for controlling immune responses. However they have been difficult to study, partly because they are quite different from those found in other parts of the body and also because they have been confused with other cell types. We have recently developed more precise methods for studying the dendritic cells which are found in the lining of the intestine, the part of the gut where most foreign materials enter and where the first decisions need to be made about how to react. This has allowed us to identify new kinds of dendritic cell which have not been studied before and whose contribution to different types of immune response is not known. In this project, we will build on this initial work to understand more about the dendritic cells found in the intestine, using a mixture of sophisticated techniques to investigate how the various groups are related to each other and to study how they each behave when tolerance or active immunity is required. We have long experience in the field and will collaborate with international leaders in Sweden, France, Belgium and the USA, giving us access to an unrivalled mixture of methods. As a result, we hope to gain unique insights into a poorly characterised population of cells of critical importance for understanding the intestine and its immune system.

Dendritic cells (DC) in the intestinal lamina propria (LP) are crucial for determining whether tolerance or active immunity is generated against the different antigens which bombard the gut. LP DC have several unique properties, including expression of CD103 and generation of retinoic acid from dietary vitamin A. It was assumed that these CD103+ DC were specialised for inducing tolerance against food proteins and commensal bacteria, whereas a distinct group of CD103- DC induced effector T cells when protective immunity is required, or when tolerance breaks down in coeliac disease or Crohn's disease. However the nature of CD103- DC in the intestine has been the subject of dispute and misconceptions, as they share markers with macrophages, which have distinct immune functions. As it is also now clear that CD103+ DC are more heterogeneous than previously suspected, the functions of LP DC in tolerance and immunity need to be explored more precisely. Recently we have developed novel strategies which allow bona fide DC to be identified accurately, finding novel populations of CD103- DC, as well as CD11b+ and CD11b- subsets of CD103+ DC. Here we will use a combination of phenotypic, genetic and functional approaches to compare how the individual subsets of DC behave in steady state intestine and in models of intestinal inflammation or after mimicking protective immunity. By studying the molecular and cellular basis of DC development in vivo and at the single cell level, we will determine how the subsets are related to each other and will examine if the unusual nature of intestinal DC reflects tissue specific precursors, or if it is "conditioned" by the intestinal microenvironment. We will then explore the local factors involved. By characterising the mechanisms controlling intestinal DC development and function under different conditions, we hope to identify targets which could be exploited for treatment of inflammatory bowel disease or for improving vaccine efficacy.

Lamina propria DC are one of the largest populations of DC in the body and are in constant contact with a vast load of antigen, but their nature and functions have been a topic of considerable debate for several years. Recently, we have developed new and more rigorous approaches which allow LP DC subsets to be identified and isolated with great precision. Here we will use these methods and other powerful techniques to understand how LP DC contribute to intestinal physiology and pathology. To our knowledge, the combination of approaches we will use are entirely unique and novel.

This proposal is a basic science research project that aims to understand fundamental processes in intestinal immunity and dendritic biology. Consequently, in the short-term, the impact of the results of the study will be most keenly felt in the academic community, and the principal beneficiaries will be immunology researchers in the UK and across the world. This will be assisted by the collaborative nature of the project, which involves links to groups in Sweden, France, Belgium and the USA, several working on tissues other than the intestine. The work will also have important implications for physicians working on inflammatory bowel disease, mucosal vaccines and on diseases whose pathogenesis is controlled by how the immune system responds to different types of antigen. These are growing areas of scientific and public interest, in which there is a dearth of sound evidence based information. As a clinically active academic, Professor Mowat has 3 CPAs in the Clinical Immunology department at Gartnavel General Hospital which is responsible for cellular phenotyping of all patients with immunodeficiency and chronic inflammatory disease in the West of Scotland. He is also engaged in a developing collaboration with Dr Richard Russell, consultant paediatric gastroenterologist at Yorkhill Hospital Glasgow, who has one of the largest clinics for children with IBD in the UK. Amongst other things, these new studies will explore the biology of dendritic cells in the mucosa of children with Crohn's disease, a topic of clear relevance to the work proposed here. We will maximise these aspects further by communicating the research through teaching and outreach activities, and by informing and educating other beneficiaries in the University and local community.

Given their fundamental nature, the proposed studies are unlikely to generate findings of direct use for treatment of disease or to the development of new pharmaceutical products in the short term. Nevertheless, there is currently great interest in the idea of targetting individual DC subsets or their markers as ways of modulating immune responses for eg treatment of cancer and inflammatory disease, or for enhancing vaccine functions. Thus identifying which DC control tolerance and immunity in the intestine could be of considerable future importance to the pharmaceutical sector and vaccine community. There are similar implications for identifying the nature of the precursors of the DC subsets, as well as understanding what local factors control their development, as the molecules and/or cells involved could provide additional targets for manipulation. It is likely that some of these markers may also ultimately be useful as biomarkers of disease staging, prognosis and treatment. If this were the case, the University has an active Research & Enterprise Office with expertise in translating basic science to clinically applicable studies. The PI has been involved in patenting and licensing intellectual property in the past, while the Centre for Immunobiology has an impressive record in carrying forward laboratory discoveries in the fields of cytokine biology, rheumatoid and respiratory disease into practice, up to the stage of ongoing clinical trials. Together this combination of personal and local expertise puts us in an excellent position to realise the clinical and/or industrial potential of the work.