The role of lipid signalling in lymphocyte activation, maturation and cell death

Gilbert, Jonathan James (1995) The role of lipid signalling in lymphocyte activation, maturation and cell death. PhD thesis, University of Glasgow.

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Lymphocytes respond to antigen receptor stimulation in a maturation stage-dependent manner. Thus, whereas mature lymphocytes become activated and proliferate in response to antigen receptor crosslinking, immature lymphocytes become unresponsive or undergo apoptosis. Initial studies, however, failed to identify any differences in the signals generated immediately following the crosslinking of antigen receptors on mature and immature lymphocytes: protein tyrosine kinase activation, inositol phospholipid hydrolysis and the mobilisation of calcium. Recent reports have indicated a key role for the stimulated hydrolysis of phosphatidylcholine in the control of a variety of cellular responses including membrane trafficking, the respiratory burst, proliferation and apoptosis. This investigation has focused on the role of phosphatidylcholine hydrolysis in the regulation of lymphocyte activation, maturation and apoptosis. Two key enzymes which mediate the hydrolysis of phosphatidylcholine are phospholipase D and phospholipase A2. Phosphatidylcholine-specific phospholipase D has been found to play a role in the transduction of intracellular signals initiated by mitogenic stimulation of a variety of cell types. This investigation has identified a number of differentially-regulated phospholipase D activities which may play key roles in mediating the transduction of mitogenic and antiproliferative signals in B cells. Initial pharmacological studies identified multiple phosphatidylcholine-specific phospholipase D activities, which were regulated by protein kinase C-, tyrosine phosphorylation- and G protein-dependent mechanisms, in B cells. However, it was found that stimulation of B cells with anti-Ig antibodies did not induce activation of phosphatidylcholine-specific phospholipase D, indicating that the B cell antigen receptor is not coupled to phosphatidylcholine-specific phospholipase D in these cells. Moreover, phosphatidylcholine-specific phospholipase D was not stimulated following crosstalk between surface immunoglobulin, interleukin-4 receptors, Class II molecules, and other T cell interacting coreceptors such as CD40, conditions designed to mimic T cell-dependent B cell activation. However, further investigation identified an as yet undefined phospholipase D activity which could be stimulated via sig on B cells, and phospholipid labelling studies indicated that this could be a phosphatidylinositol-specific phospholipase D activity. Further investigation of the role of phosphatidylcholine-specific phospholipase D found that stimulation of B cells with adenosine trisphosphate induced phosphatidylcholine-specific phospholipase D activation. The findings of this investigation therefore strongly implicate the antigen receptor-mediated release of arachidonate in the induction of growth arrest and/or apoptosis. Furthermore, sphingomyelinase, a signal transducer which has been shown to be activated by released arachidonate in other cell types, was found to be temporally downstream of cytosolic phospholipase A2 activation following crosslinking of the antigen receptors on WEHI 231 immature B cells.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Immunology.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Harnett, Maggie
Date of Award: 1995
Depositing User: Enlighten Team
Unique ID: glathesis:1995-71524
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 14:24
Last Modified: 20 Aug 2021 13:08
Thesis DOI: 10.5525/gla.thesis.71524

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