The role of T cells in epithelial maintenance and regeneration. (360G-Wellcome-106089_Z_14_Z)

The key goal of my proposed research is to examine whether T cells are able to regulate epithelial behaviour of the gut and skin via provision of signals through epithelial TNFR and subsequent activation of the alternative NF-kappaB signalling pathway and resulting transcription network. Strong evidence from other epithelial tissues indicates that T cells signal through these receptors to regulate epithelial behaviour, including in thymic epithelium where these T cell mediated signals are requi red to drive normal epithelial development(1). In other instances these signals may be mis-appropriated, with pathological consequences (for example Treg RankL driven mammary breast cancer metastasis) (2). My key goals are 1. To examine TNFR expression by gut and skin epithelium in normal homeostasis and during inflammation and subsequent repair. The expression of TNF ligands on T cell subsets within gut and skin will be examined in parallel. 2. To determine the roles of these receptors in models of gut and skin inflammation and subsequent epithelial recovery, by deletion of receptors in epithelial subsets using conditional mouse knockout models. 3. To determine the role that alternative NF-kappaB signalling plays in skin and gut epithelium inflammation, healing and homeostasis, by constitutively switching on this pathway in epithelial subsets.