Crompton, Tessa; (1990) Cell death in the immune system. UNSPECIFIED thesis (Ph.D.), University College London.

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Abstract

A distinction based on morphological criteria has been made between two forms of mammalian cell death: necrosis, which is mediated by agents external to the cell, and apoptosis, which is believed to be the result of the triggering of an active suicide mechanism in a cell that dies as a result of a physiological, developmentally-regulated process. In the immune system, apoptosis has been implicated as a mechanism of thymic selection and of cytotoxic T lymphocyte (CTL) killing. DNA fragmentation is regarded as a hallmark of apoptosis. This thesis examines three forms of cell death in the immune system. First, I show that the cell death induced by the removal of the specific growth factor from IL2- and IL3-dependent cell lines falls into the category of apoptosis, as defined morphologically. The DNA is cleaved into nucleosome-sized pieces and survival is enhanced by the nuclease inhibitor aurintricarboxylic acid and by protein synthesis inhibitors. The effect of the protein synthesis inhibitors does not seem to be due to partial cell cycle arrest, as synchronization of the cells does not alter the kinetics of death. Second, in an attempt to confirm a report that acquisition of resistance to glucocorticoids correlates with acquisition of resistance to CTL killing, I isolated a series of dexamethasone (dex)-resistant mutants from a dex-sensitive clone of the mastocytoma P815 and tested them for susceptibility to killing by CTL. I have used Northern-blot analysis, with a probe to the glucocorticoid receptor, to see if dex resistance is due to a loss of receptor expression or to an increased ability to down- regulate receptor expression. Third, I have developed an assay to measure the extent of apoptosis in a tissue in vivo, using radiolabelled DNA precursors. Apoptosis was shown to be induced in double positive thymocytes in vivo by injection of a monoclonal antibody anti-CD3.

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