Human T lymphocyte trafficking in large airways and alveoli: the role of lymphocyte adhesion, the epithelial cytoskeleton and the Rho family of GTPases. (360G-Wellcome-064961_Z_01_C)

In healthy individuals there is a continual flux of leukocytes to and from the alveoli and large airways and this constitutive trafficking is increased in response to infectious and allergenic stimuli. Although much is known of leukocyte adhesion to the vascular endothelium and transendothelial migration. By comparison, little is known of leukocyte interactions with the basal surface of the epithelium or of subsequent passage across the epithelial barrier. Epithelial integrity is maintained by the apically placed tight junction together with the more basally placed adherens junction which, linked via the cytoskeleton, together form the functional apical junction complex (AJC). It is across the AJC that transmigrating leukocytres must pass. Data suggest that leukocytes can interact with epithelial cells to influence the AJC but it is not clear which signalling pathways are involved; although there appears to be a requirement for integrin-mediated adhesion of the leukocyte to the epithelium. Accumulating evidence suggests that the Rho-family of small GTPases (Rho-GTPases) can alter AJC permeability both indirectly, via their known effects on the actin cytoskeleton, and directly via effects on epithelial junctional molecules. In addition, there is evidence that Rho acts downstream of the integrin ligand intercellular adhesion molecule (ICAM)-1 on endothelial cells. We propose that adherent leukocytes interact with epithelial adhesion molecules to initiate downstream signalling events that involve the Rho-GTPases and result in alterations in the actin cytoskeleton and the AJC to facilitate and regulate leukocyte passage. This project will combine the candidate's previous experience in integrin-mediated adhesion, T cell biology and the respiratory epithelium with the expertise of the proposed host laboratory in signalling, cytoskeletal rearrangements and the Rho family of GTPases to address a fundamental question in cellular immunobiology.