Chemokines and Integrins in Lymphocyte Development and Localization

Abstract: The small intestine contains a large number of T lymphocytes within the single-layered epithelium that separates the gut lumen from the lamina propria. These intraepithelial T lymphocytes have potent cytolytic and immunoregulatory capacities, thought to be important for fighting infections, neoplastic growth, and sustaining epithelial integrity. This thesis is based on three original articles with the overall aim to examine mechanisms directing lymphocyte development, localization, and population maintenance in the intestinal mucosa, with particular focus on the potential roles of the chemokine/chemokine receptor pair CCL25/CCR9 and b1 integrins in these processes. In addition, this thesis contains an overview of published work examining the roles of integrins and chemokines in T lymphocyte trafficking, and thymic and extrathymic T lymphocyte development. One hypothesis in the field of intestinal intraepithelial lymphocyte (IEL) homeostasis has been that b1 integrins play an important role in maintaining IEL in the epithelium. We show here that the absence of b1 integrin does not affect the numbers or subset composition of intestinal IEL, suggesting that there is a remarkable capacity for compensatory mechanisms in the homeostasis of the gut immune system, that may have been underestimated previously. Furthermore, we show that CCL25 is crucial in the generation of the intestinal CD8aa+ IEL compartment. By using a competitive hematopoietic stem cell adoptive transfer system we demonstrate that CCR9 plays an important role in both thymic and extrathymic T lymphocyte development. In the case of thymic T lymphocyte development preliminary data suggest that CCR9 functions after thymic progenitor entry into the thymus. Together, these studies further establish CCL25/CCR9 as key players in thymic and intestinal T lymphocyte development and/or trafficking.