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Investigation of Events Downstream of T Cell Receptor-Signalling in T Cell Development, Selection, and Differentiation

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Investigation of Events Downstream of T Cell Receptor-Signalling in T Cell Development, Selection, and Differentiation Investigation of events downstream of T cell receptor-signalling in T cell development, selection, and differentiation A Dissertation Presented By Paz Prieto Martín Submitted to the Department of Life Sciences, Faculty of Sciences Imperial College of London for the degree of DOCTOR OF PHILOSOPHY 2017 IMMUNOLOGY Declaration of Originality I state that this work is my own and that I have appropriately referenced all external sources in the text. Copyright declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. Acknowledgements I have to say that completing a PhD is being a very challenging journey. I would not have been able to accomplish it without the support of my supervisors, Masahiro Ono and Tessa Crompton. To both of them, all my gratitude. Thank you to all colleagues and friends at UCL and Imperial College, specially to David Bending for bringing to our group both his expertise and his friendship. I also deeply appreciate the support of the staff at the flow cytometry facilities and biological services at UCL and Imperial College, always kind and helpful. It has been a long path from when I first finished my Biology studies at the University of Alcalá, in 2002. I started to do research in immunology through my Masters degree in the same university. From that time, my deepest thanks to Espe Perucha, for being my best research teacher and for her contagious passion for research. Thank you also to María Hernández and the late Eduardo Reyes, for the best recommendation letter ever for doing research in Japan, and for being always positive. Thanks to them and the Ministry of Education of Japan, I went to Kyoto University as a research student. I was always lucky to have great team members and co-workers to look up to. Thanks to all of them. Thanks a lot to Shimon Sakaguchi for welcoming me into his group. Thanks also to Kajsa Wing, thanks for her patience and her support. All my appreciation as well to Yaguchi-san, Shibata-san and Yoshioka-sensei for their unconditional support inside and outside of the lab. My gratitude also to my brother Alfredo Prieto, who used to bring me as a child (together with other brothers and sisters) to the lab on week-ends, when he was doing his PhD (those old times). Thank you for being there. And thanks to all members of my big family. Last but not least, a big hug for Kike Santos, my loving partner, always by my side, helping me to keep my sanity during the hardest times, and sharing every good and bad moment. Thanks also to the examiners for their helpful discussion during the viva and their comments. Finally, thanks to all and everyone involved in any way with this project. Sorry, I almost forgot to say thank you to you, my reader. I hope you find this work interesting and helpful. My best wishes. Abstract T cell development and differentiation are dependent on T cell receptor (TCR) signalling. This project investigates the events downstream of TCR-signalling in CD4+T cell development and differentiation by studying the transcriptional dynamics of two key genes in individual cells: an immediate early transcribed gene upon TCR engagement (Nr4a3) and a more lately transcribed gene following TCR signalling (Foxp3). Because there were no technologies to study those transcriptional dynamics in vivo in individual cells, a new reporter technology (a fluorescent timer protein called Timer) was used. The first part of this project establishes two new transgenic mouse strains expressing Timer fluorescent protein, Nr4a3Timer and Foxp3Timer. Several independent reporter lines were assessed by their Timer expression, and selected. The second part studies the dynamics of Timer protein expression in the selected transgenic strains. An analysis framework was established to reveal the dynamics of expression of the reported genes (Nr4a3 and Foxp3) by using the expression and colour maturation of Timer. The last part of the project was dedicated to addressing biological questions using our new fluorescent reporter strains. First, I used the Timer technology to investigate the temporal dynamics of Nr4a3, CD25 and Foxp3 expression during neonatal thymocyte development upon TCR signalling. This information placed CD25 expression as an early event downstream of TCR signalling, while Foxp3 expression appeared later on, with or without coexpression of CD25. Second, the investigation of the mechanisms downstream of TCR-signalling in peripheral CD4+ T cells in vitro showed the modulatory role of IL-6 and TGFβ on Nr4a3 expression. Finally, investigation of the role of Nr4a3 overexpression in T cell apoptosis showed that Nr4a3 proapoptotic effects are context- dependent, depending on the cytokine environment. This project constitutes the first application of a fluorescent timer reporter system to the field of T cell immunology. It also provides a better understanding of the role of Nr4a3 in TCR-mediated events in T cell differentiation and activation. Contents Declaration of Originality 2 Copyright declaration 3 Acknowledgements 4 Abstract 5 List of Figures 9 List of Tables 13 Nomenclature 14 Introduction 18 Adaptive immune system and CD4+T cells . 18 Nr4a3 . 35 Methods for measurement of protein expression dynamics. Timer technology 41 Thesis aims . 47 Methods 49 Transfection of HEK 293T cell line . 49 Mouse strains . 50 Molecular biology techniques . 50 Neonatal analysis . 53 CD4+T cell differentiation cultures . 53 Flow cytometry . 54 6 CONTENTS 7 Cell counting . 56 Data visualisation . 57 Flow cytometric data analysis . 57 Statistical analysis . 59 1 Establishment of two new transgenic reporter mouse strains 61 1.1 Introduction . 61 1.1.1 Generation of BAC transgenic Timer reporter strains . 62 1.1.2 Generation of new BAC Tg mice lines for Nr4a3 and Foxp3 ... 64 1.2 Assessing the expression of the Timer protein by flow cytometry . 65 1.3 Establishment of independent lines . 66 1.4 Determination of copy number . 68 1.5 Determination of homozygosity or heterozygosity . 70 2 Dynamics of Timer expression in Nr4a3Timer and Foxp3Timer CD4+T cells 73 2.1 Introduction . 73 2.2 Timer maturation analysis through neonates data . 74 2.2.1 Data transformation: Timer angle (θT imer) and Timer intensity (IT imer)................................ 78 2.2.2 Trajectories of cells through Timer bi-dimensional space (Timer blue-red) . 82 2.3 Discussion . 87 3 Differentiation of Foxp3+ regulatory T cell in the thymus 89 3.1 Introduction . 89 3.2 Results: Investigation of TReg differentiation in the thymus . 92 3.2.1 Neonatal CD4SP thymocytes analysis . 93 3.2.2 TReg precursors in neonatal thymus . 99 3.2.3 CD5 expression during CD4SP development . 110 3.2.4 Alternative TReg precursors: CD25-Foxp3+ cells . 113 3.2.5 CD4+ T cells in the Spleen during ontogeny . 116 3.2.6 Timing of Foxp3 transcription during TReg development in Foxp3Timer:Foxp3GFP reporter mice . 123 CONTENTS 8 3.3 Discussion . 124 3.3.1 Dynamics of Foxp3 and Nr4a3 expression . 129 3.3.2 Foxp3: lineage and feedback control . 130 4 The effect of cytokines and costimulation on Nr4a3 transcription 131 4.1 Introduction . 131 4.2 In vitro study of T cell differentiation and TCR signalling . 133 4.2.1 Effects of IL-6 and TGF-β on Nr4a3 expression . 136 4.2.2 Effects of costimulation (CD28) on Nr4a3 expression . 141 4.3 Effects of Nr4a3 overexpression on in vitro T cell differentiation . 145 4.3.1 Tetracycline inducible expression of Nr4a3 (NIGrtTA) . 146 4.4 Discussion . 155 4.4.1 Regulatory effects of the cytokines IL-6 and TGF-β on Nr4a3 expression . 156 4.4.2 Effects of Nr4a3 overexpression on Foxp3 and IFNγ ....... 158 4.4.3 CD28 signals alter the dynamics of expression of Nr4a3 . 159 5 Investigation of the role of Nr4a3 in apoptosis 161 5.1 Introduction . 161 5.2 Nr4a3 overexpression effect on AICD . 162 5.3 Investigating the effects of Nr4a3 overexpression on RICD . 170 5.4 Discussion . 173 Conclusions 174 Future directions 179 Bibliography 181 Appendices 190 A Plasmids . 190 B Gating strategy R . 191 List of Figures 1 TCR interactions in the cortex and the medulla . 20 2 Thymocyte development . 25 3 Thymocyte development check points . 27 4 Nr4a3 structure . 36 5 Dynamics of EGFP maturation scheme . 43 6 Timer and EGFP fluorescent properties . 45 7 Fluorescent Timer maturation scheme . 46 1.1 Establishment of BAC tg lines . 63 1.2 Timer plasmid transfected HEK cells scatter plot . 66 1.3 Agarose gel of reporter founder mice . 67 1.4 Copy number from qPCR . 69 1.5 Flow cytometry data of homozygous and heterozygous Nr4a3Timer ... 70 1.6 Mean fluorescence intensity (MFI) of Timer blue and Timer red in ho- mozygous and heterozygous Nr4a3Timer mice . 71 1.7 Percentages of Timer blue and Timer red cells in homozygous and heterozygous Nr4a3Timer mice . 72 2.1 Patern of expression of Timer blue and Timer red forms in CD4+ cells from thymus and spleen of Nr4a3Timer mice after birth . 75 2.2 Patern of expression of Timer blue and Timer red forms in CD4+ cells from thymus and spleen of Foxp3Timer neonates . 75 2.3 Gating strategy for Nr4a3Timer ........................ 77 2.4 Reference population gating strategy for Foxp3Timer ............ 77 2.5 Timer angle definition . 79 9 LIST OF FIGURES 10 2.6 Geometric explanation of Timer intensity and Timer angle .
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