Investigation of the signal transduction pathways involved in the induction of T-lymphocyte motility

Dixon, Richard (1996). Investigation of the signal transduction pathways involved in the induction of T-lymphocyte motility. PhD thesis The Open University.



Induction of lymphocyte motility is an essential early step in extravasation of lymphocytes into inflammatory sites and also into lymphoid tissues in the process of lymphocyte recirculation. Lymphocyte motihty requires a change from a spherical morphology to a constantly changing irregular shape. In this study, a variety of agents have been investigated for induction of this shape changing morphology in freshly isolated human peripheral blood T-lymphocytes (PBTLs) and a non-motile variant of the MOLT-4 human lymphoid cell line. The MOLT-4 cells proved to be non-responsive to most of the agents tested, however, 5 agents were found to cause significant polarisation in PBTLs. IL-2, IL-15, fetal calf serum (PCS) and nocadazole induce shape change in 20-40% of PBTLs. However, the most potent inducer of shape change found were the PKC inhibitors of the bisindolylmaleimide (Bis) type, which show effects on over 60% of PBTLs, as reported recently. Do these diverse inducers of shape changing in PBTLs act by a common signal transduction pathway? With IL-2, IL-15, PCS, nocadazole and Bis., no common changes in intracellular calcium flux, intracellular pH, inositol triphosphate levels, renaturable kinase activity and tyrosine phosphorylation have been found. So if a final common signaltransduction pathway exists, it must involve other second messenger systems.

However, a number of pharmacological agents were found to prevent the induction of shape change in PBTLs, indicating that they could be targeting a common second messenger element involved in motility signal transduction. Comparisons of their chemical structures revealed no common structural motifs that would explain their common effects on lymphocyte motility

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