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Cell Death in the Immune System CELL DEATH IN THE IMMUNE SYSTEM Tessa Crompton Imperial Cancer Research Fund Tumour Immunology Unit Department of Biology University College London A thesis submitted for the degree of PhD University of London 1990 1 ProQuest Number: 10609764 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10609764 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ACKNOWLEDGEMENTS I would like to thank the members of the Biology department, Medawar building, for discussions and assistance, in particular Avrion Mitchison, Benny Chain, Nigel Pringle and Liz Thompson. Above all, I would like to thank Martin Raff for his help and support. I thank Bob Miller for advice on electron microscopy, Peter Karran for advice on DNA-repair enzyme assays, and Andrew Wyllie for helpful discussions. I thank Martin Raff and Avrion Mitchison for critical reading of this manuscript. 2 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 Northem-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. 3 TABLE OF CONTENTS T itle Page .............................................................................................................................1 Acknowledgements .................................................................................................2 A bstract...................................................................................................................... 3 Table of contents .................................................................................................. 4 List of Illustrations .............................................................................................. 5 Abbreviations ...........................................................................................................7 Chapter One: General Introduction ...........................................................9 Programmed cell death in C. elegans........................................................10 Cell death in vertebrates ................................................................................ 12 Apoptosis in the murine immune system ............................................. 20 Chapter Two: Materials and Methods .....................................................27 Cell culture ............................................................................................................30 Assessment of cell viability ..........................................................................35 Transmission Electron Microscopy ........................................................... 37 Biochemistry ......................................................................................................... 39 Molecular Biology .............................................................................................40 Bacteriological Methods .....................................................................................46 Chapter Three: Death of growth factor dependent cell lines .................................................................................................................49 Introduction ............................................................................................................ 50 R esults .......................................................................................................................51 Discussion ................................................................................................................ 82 Chapter Four: Do CTL killing and glucocorticoid-induced lysis share a common pathway? ................................................................. 88 Introduction ............................................................................................................ 89 R esults .......................................................................................................................92 Discussion .............................................................................................................. 114 Chapter Five: Studies on apoptosis in the thymus ........................120 Introduction............................................................................................................121 Results: Development of an assay for apoptosis in vivo............... 130 Effect of mab anti-CD3 on thymocytes in vivo..................................... 146 Apoptosis in immature thymocytes in vitro........................................ 149 Discussion .............................................................................................................. 162 Chapter six: General Conclusions ............................................................166 Bibliography ..........................................................................................................168 4 LIST OF ILLUSTRATIONS Fig. 1 Kinetics of death of FDCP-2 cells (a) and CTLL cells (b) on withdrawal of growth factor. 52-53 Fig. 2 Electron micrographs of FDCP-2 cells, 20 h after IL3 removal (a-d), cultured with IL3 (e) and after complement and antibody treatment (f). 56-59 Fig. 3 DNA fragmentation in FDCP-2 cells. 61-63 Fig. 4 and 5 Effect of ATC on the survival of FDCP-2 cells after IL3 withdrawal. 69-70 Fig. 6 and 7 Effect of cycloheximide on the survival of FDCP-2 cells after IL3 withdrawal. 71-73 Fig. 8 Flow cytometry of FDCP-2 cells to assess cell cycle status.75 Fig. 9 Kinetics of death of FDCP-2 cells on IL3 removal after separation according to size, and analysis of cell cycle status. 76 Fig. 10 Effects of hydroxyurea and aphidicolin on proliferation of FDCP-2 cells. 78-79 Fig. 11 Kinetics of DNA fragmentation of A4 cells after separation according to size, and cell cycle analysis. 80 Fig. 12 Activity of O^MeG-DNA methyltransferase in extracts of FDCP-2 cells and CTLL cells. 81 Fig. 13 Death of P815a cells after culture in dexamethasone. 93 Fig. 14 Agarose gel of DNA prepared from P815a cells grown in dex, showing DNA laddering. 94 Fig. 15 CTL killing of P815a cells. 95-96 Fig. 16 Proliferation of clones selected from P815a, after 3 days culture in dex. 101-103 Fig. 17 CTL killing of clones of P815a. 104 Fig. 18 Kinetics of DNA fragmentation in CTL killing of P815a. 105 Fig. 19 Proliferation of clones of P815a after 3 days of culture in dex, after 5azaC treatment. Ill Fig. 20 Northern blot analysis of glucocorticoid receptor mRNA in dex-sensitive and dex-resistant clones of P815a. 112-113 Fig. 21 In vivo labelling of thymocytes with ^HTdR (a and b) and 125IUdR (c). 134-135 Fig. 22 Tissue distribution of radiolabel after in vivo labelling with 3RTdR (a) and 125IUdR (b). 141 5 Fig. 23 Decline of radiolabel in vivo in thymus (a) and lymph nodes (b). 142 Table 1 Estimation of the degree of DNA fragmentation in thymuses and lumph nodes of mice that have been prelabelled with 125lUdR (a and b) and 3HTdR (C and d). 143-144 Fig 24 In vivo DNA fragmentation in thymus and lymph nodes of mice after hydrocortisone treatment. 145 Fig. 25 DNA fragmentation after in vivo anti-CD3 treatment 152 Fig. 26 Effects of in vivo anti-CD3 treatment on thymocytes, assessed by folw cytometry. 153-156 Fig. 27 Agarose gel of DNA from mice injected with anti-CD3 or anti-CD4 mab, showing that anti-CD3 mab causes DNA fragmentation in the thym us.
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