Regulation of intestinal T cell homeostasis by autophagy

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 bacteria (microbiota). We must be tolerant to these beneficial antigens, while at the same time being ready to respond to antigens derived from pathogens that try to invade through the
intestine. Several regulatory mechanisms operate to maintain immune homeostasis in the gut and when these are altered or dysfunctional, harmful inflammatory responses can arise, leading to inflammatory bowel diseases (IBD) or food allergies.
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). Moreover, it has alsobeen proposed that IECs can present antigen in the context of MHC-II molecules and thereby
influence local CD4+ T cell responses in an antigen specific manner.

This could be of great importance in the context of IBD because although pathology is driven by aberrant CD4+ T cell responses, the influence of IEC on these pathogenic T cell responses is not known. 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 plan to use a recently established Ǯorganoid ǯmodel 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 effects of IEC antigen presentation, particularly
the consequences on the T cell compartment and the impact on intestinal inflammation, such as human IBD.