Chemokine Receptor CCR9: Studies on the Generation and Localization of Gut Tropic Lymphocytes

Abstract: Lymphocytes are important mediators of adaptive immune responses. Naive T lymphocytes circulate in the blood and lymph between different secondary lymphoid organs in search for their specific antigen. Upon activation, lymphocytes change their expression of adhesion molecules and chemokine receptors and become able to enter non-lymphoid tissues where they take part in fighting infections. Selective migration of lymphocytes is regulated by interactions between distinct surface expressed adhesion molecules and chemokine receptors on lymphocyte subsets and their specific ligands expressed on blood vessel endothelial cells and within tissues. The chemokine CCL25 is selectively and constitutively expressed by human small intestinal epithelial cells and its receptor, CCR9 expressed on small intestinal lymphocytes and a peripheral blood memory T cell population co-expressing markers associated with gut tropism. Together these observations suggest an important role for CCL25 and CCR9 in small intestinal immunity. In this thesis, we have investigated the mechanism involved in the generation and localization of CD8ab gut tropic T cells. We have found that; i) CCL25 and CCR9 play an important role in the localization of CD8ab T cells to the small intestinal epithelium; ii) gut tropic CCR9 a4b7 CD8ab T cells are selectively generated in mesenteric lymph nodes (MLN) by MLN dendritic cells (DCs); iii) MLN DC-induced CCR9 and a4b7 expression requires a soluble factor generated in MLN DC:T cell co-cultures in an antigen dose dependent manner.