Intestinal classical Dendritic cells in T cell induced colitis and colitis associated colorectal cancer

Abstract

Our intestinal tract works hard for us continuously, it helps us take up important nutrients, vitamins and minerals from the food we ingest. Some of these processes take place with the help of an estimated amount of 1014 "good" microorganisms such as bacteria that ferment fiber. The immune system that is present in the intestinal wall has the complex task to distinguish between the beneficial food derived molecules and "good" microorganism and detrimental pathogens. Failure to maintain this balancing act, known as homeostasis, in combination with environmental factors and genetic predisposition can lead to chronic inflammatory bowel disease (IBD) such as Crohn's disease and Ulcerative colitis. Moreover, patients with IBD may develop inflammation induced colorectal cancer (CRC) when they have a genetic predisposition or when IBD treatment fails. Classical dendritic cells (cDCs) are an important part of the intestinal immune system. cDCs are specialized 'sensors' that can recognize patterns and molecules (known as antigens) that are derived from pathogenic bacteria, good bacteria, the body's own cells and food with the help of a broad spectrum of different receptors that these cDCs express. Upon recognition of antigens the dendritic cells can activate specialized T cells that can either help clear detrimental pathogens/ tumor cells or prevent an immune response towards beneficial bacteria/ food derived molecules. In the intestine 2 main types of cDCs are present: cDC1 and cDC2. cDC1s are important in activating T helper 1 (Th1) cells that produce IFNγ which are important in the defense against parasitic and intracellular infections and in parts of the intestine they can induce regulatory T cells that possibly reduce responses to our own cells and food derived antigens. In other parts of the body cDC1s have been shown to activate Th1 cells and cytotoxic T cells with anti-tumor properties. cDC2 cells play a role in activating T helper 17 (Th17) cells and T helper 2 (Th2) cells, the former have different roles in maintaining homeostasis in the intestine while the latter are important for the defense against parasitic infections. To date however the role that cDC1s and cDC2s have in intestinal inflammation and CRC remains to be elucidated. In the current thesis I assessed the role of cDC2s in an experimental model of T cell induced colitis and the role of cDC1s in an experimental model of inflammation induced CRC. T cell induced colitis is thought to be dependent on a subset of proinflammatory Th17 cells. In manuscript I we showed that cDC2 cells play a role in the initiation phase of colitis development but were redundant once disease progressed. We suspect that the inflammatory environment attracts another type of inflammatory dendritic cells that is capable of inducing and maintaining proinflammatory T cells. Manuscript II describes that cDC1 cells have no significant role in inducing an anti-tumor response in a mouse model of inflammation induced CRC In the absence of cDC1 cells, despite a reduction in Th1 cells, mice developed tumors similar to mice that had normal amounts of cDC1 cells.