EFFECTOR T CELL HOMING TO THE SMALL INTESTINAL MUCOSA

The intestinal mucosa, including the intestinal epithelium and underlying lamina propria (LP), contains a large number of effector/memory T cells that are thought to play a central role in the generation and maintenance of mucosal immune responses and in maintaining mucosal integrity. The work in this thesis investigates the mechanisms regulating effector T cell recruitment to the small intestinal mucosa focusing on the role of chemokine receptors in this process. Firstly, we aimed at determining chemokine receptors involved in the localization of CD4+ T cells to the small intestinal LP. We show that endogenous CD4+ lamina propria lymphocytes (LPLs) express a heterogeneous array of chemokine receptors including CCR9, CCR6, CCR5, CXCR6 and CXCR3. Furthermore, since CCR9 was shown to be selectively induced on CD4+ T cell activated in mesenteric lymphnodes and expressed on the majority of CD4+ T cells entering into the small intestinal LP, CCR9 was suggested as a candidate receptors involved in migration to the intestinal LP. The importance of CCR9 was examined in competitive adoptive transfers with CCR9-/- and WT CD4+ T cells demonstrating both CCR9 dependent and independent CD4+ T cell entry in to the small intestinal LP. Secondly, we demonstrate differences in the CCR9 dependent CD8??+ T cell localization both within and to the separate sites along the length of the small intestinal epithelium. The CCR9 dependent migration was shown to be more efficient to the proximal compared to the distal small intestinal mucosa, corresponding to higher epithelial expression levels of the CCR9 ligand CCL25 at this site. Migration of cells to the LP was less dependent on CCR9 than migration to the epithelium. Finally the CCR9 independent migration to the LP was found to be pertussis toxin sensitive, suggesting a role for additional G?i linked G protein-coupled receptors