Comparison of intestinal APC subsets from homeostatic and immunostimulatory environments
Antigen presenting cells (APC) including dendritic cells (DC) play a key role in the initiation and direction of adaptive immune responses. Acting as sentinels in the tissue, DC sample antigen and traffic to the local lymph node where they present antigen to naïve T cells. The signals DC provide to naïve T cells determines the functional fate of the T cell and therefore, the type of immune response generated. At mucosal sites, such as the intestine, immune responses need to be carefully regulated due to the high antigenic load. For this reason, intestinal immune cells are highly specialised to prevent immune activation to innocuous antigens while still holding the capacity to induce potent responses to pathogenic microbes and helminths. Oral administration of antigen is associated with tolerance and the generation of FoxP3+ regulatory T cells (Tregs). Specialised lamina propria (LP) resident APC are required for the initiation of Treg differentiation in the mesenteric lymph nodes (MLN) through production of chemical mediators such as retinoic acid (RA). Ablation of these populations or restricted trafficking prevents the development of Tregs in mouse models thus supporting the essential role of APC in maintaining intestinal homeostasis. During infection, APC promote the induction of adaptive immune responses which neutralise threats. However, the APC subsets involved in this are not well defined. Pathologies such as food allergy and inflammatory bowel disease are thought to arise due to the development of aberrant immune responses. Food allergy can be modelled in mice using the mucosal adjuvant cholera toxin (CT) which has been shown to drive immunity to co-delivered antigens and is associated with the generation of IL-4 producing T helper 2 cells. Understanding the APC subsets involved in the initiation of intestinal immune responses could help in the development of targeted therapies for inflammatory bowel conditions. In this thesis, I show that oral administration of CT is followed by the appearance of a novel phenotype of DC in the intestinal LP and MLN. These DC differ functionally from DC at steady-state and may contribute to the generation of IL-4 producing T cells observed in the LP, MLN and spleen following oral administration of CT.