Antigen presentation and T cell regulation by intestinal epithelial cells

The intestinal tract presents a unique challenge to the immune system because it is a site of constitutive exposure to large amounts of foreign antigens, mainly derived from dietary sources and commensal microbiota. Several regulatory mechanisms operate to maintain immune homeostasis in the gut and when these are dysfunctional, harmful inflammatory responses can arise, leading to inflammatory bowel diseases (IBD). A single layer of intestinal epithelial cells (IECs) separate the luminal microbiota from the underlying leukocytes, therefore defects or lesions of the epithelial barrier are strongly linked to the development of IBD (Maloy and Powrie, 2011). However, in addition to barrier function, the IEC layer also participates in active regulation of the immune response, for example, through expression of chemokines and adhesion molecules that recruit leukocytes during inflammation (Pott and Hornef, 2012). In this project we aim to analyse the IEC response towards inflammatory stimuli and to functionally address the cross-talk between IEC and CD4+ T cells in the colon at steady-state and during intestinal inflammation. We will focus the investigation particular on antigen-specific MHCII mediated interaction. We plan to use a recently established 'organoid' model to study the interaction between primary IECs and T cells ex vivo. This will be combined with a genetic approach to selectively delete MHC-II molecules in IECs and to analysis of T cell compartments at steady state and in models of chronic and acute colitis. Together, these experiments will reveal a more comprehensive picture on the role of IECs in coordinating the mucosal immune response, particularly the consequences on the T cell compartment and the impact on intestinal inflammation, such as human IBD.