Expression and regulation of CCL25 and its role in T cell localization to and function within the small intestine

Abstract: Earlier studies have demonstrated an important role for the chemokine CCL25, and its receptor CCR9, in the generation of the small intestinal lymphocyte compartment. The work in this thesis was aimed at determining how CCL25 is regulated within the small intestinal mucosa, and what potential role it plays in T cell localization to and function within this site. We have identified epithelial cells as the main source of CCL25 mRNA in the small intestine, and also defined the CCL25 minimal promotor. CCL25 expression was independent of signaling through the lymphotoxin b receptor (LTbR) and inflammatory stimuli, which are signals regulating other chemokine genes. Instead, we suggest a novel role for the caudal related homeobox transcription factors Cdx-1 and Cdx-2 in driving small intestinal CCL25 expression. We have also showed that CCL25 promotes the induction and function of the integrin CD103 on small intestinal IEL. CD103 interacts with E-cadherin on epithelial cells, and by modulating this interaction CCL25 may regulate IEL-epithelial cell interactions and thus have effects on both IEL and epithelial cell function in the small intestine. Finally, we examined the role of CCL25/CCR9 in CD4 T cell localization to the small intestinal lamina propria and demonstrate both CCR9 dependent and independent mechanisms for CD4 T cell entry into the this site.