Previous and current research
Leukocytes are motile cells which circulate in the blood stream until responding to tissue signals. By binding to ICAM-1, the integrin LFA-1(αLβ2;CD11a/CD18) mediates many adhesive interactions necessary for the function of leukocytes. Integrins on leukocytes are normally in an inactive state, preventing random interactions, and are activated via triggering through other receptors. We have found that many agonists cause LFA-1 clustering and that this clustering increases the ability of the cell to bind ligand. Recently we have had insight into the mechanisms of integrin activation through investigation of an unusual patient with an integrin dysfunction affecting β1, β2 and β3 integrins. Surprisingly this lesion causes inactive but constitutively clustered integrin, suggesting a fault in the regulation of clustering.

Another area of interest is to identify the signals that LFA-1 sends into cells and also their functional consequences. We have discovered that when T cells attach to ICAM-1, the acto-myosin machinery is activated and the cells rapidly migrate with an average speed of ~10.5 mm/minute. Myosin motor activity is controlled at the leading edge by myosin light chain kinase and at the trailing edge by Rho kinase. How LFA-1 might control these two compartments of motor activity is a question of interest. Recently we have observed that high affinity, clustered LFA-1 is localised to a special structure on the migrating T cell that we have termed the focal zone. Characterisation of the focal zone is a key goal.

A different lab topic concerns two small heterodimeric S100 family proteins MRP-8 and MRP-14 which represent ~40% of neutrophil cytosolic protein. These proteins appear to be deposited on stimulated endothelium in association with transmigrating leukocytes. We have made MRP-14 null mice and are presently investigating them for clues of MRP-14 function. The lack of MRP-14 protein results in instability of its partner MRP-8 and, amazingly, the loss of this heterodimer has no impact on other neutrophil proteins nor on the lifespan of the average neutrophil!

Future projects
We are interested in the consequences of LFA-1 signalling into T cells and aim to dissect the relevant pathways leading to T cell migration. We have also characterised LFA-1 null mice and are exploring in vivo roles for LFA-1 in leukocyte migration and in control of key immune responses. We continue to explore the function of murine MRP-14 and MRP-8 using models which will allow us to examine their functions in vivo.