Porter, Joanna Catherine Mary; (1998) Control of leukocyte integrin activity on T lymphocytes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The control of lymphocyte extravasation from the circulation into sites of inflammation is critical for the co-ordination of an appropriate and effective immune response. Much previous work has focused on how leukocytes cross the endothelial barrier, but there has been less emphasis on subsequent events. This thesis aims to investigate aspects of adhesion involved in the migration of extravasated leukocytes across the extracellular matrix. The integrin family of cell surface receptors are a major family of lymphocyte adhesion molecules involved in these events. It is already well established that lymphocyte integrins are not constitutively active and require activation before being able to bind to their ligands. Such activation can be achieved by signals received by the T lymphocyte through its cell surface receptor, the T cell receptor (TCR/CDS) complex, and also by direct effects of cations on the integrin ectodomain in the absence of an intracellular signal. In this thesis, I describe experiments examining the interaction of human T lymphocytes with respiratory epithelial cells and with components of the extracellular matrix, such as collagen and fibronectin, following various methods of integrin activation. In particular, I present the first direct evidence for crosstalk between [beta]2 and [beta]1 integrins on T lymphocytes. A model of lymphocyte extravasation is proposed in which cross-talk co-ordinates sequential integrin activation and successful transmigration. In addition, this thesis also includes work aimed at defining signalling pathways involved in the activation of the [beta]2 and [beta]1 integrins following TCR/CD3 engagement, and the role of the lymphocyte cytoskeleton in such integrin activation. In summary, I have described aspects of the control of leukocyte integrins on T lymphocytes following various different stimuli, and the role of this controlled activation in successful T lymphocyte migration.

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