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Natural Killer Cell: Repertoire Development, Education and Activation Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2016 Natural Killer Cell: Repertoire Development, Education and Activation Landtwing, Vanessa Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-136828 Dissertation Originally published at: Landtwing, Vanessa. Natural Killer Cell: Repertoire Development, Education and Activation. 2016, University of Zurich, Faculty of Science. Natural Killer Cell: Repertoire Development, Education and Activation Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr.sc.nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät Der Universität Zürich von Vanessa Sonja Landtwing von Zug ZG Promotionskomitee Prof. Dr. Christian Münz (Vorsitz, Leitung der Dissertation) Prof. Dr. med. Markus Manz Prof. Dr. Werner Held Zürich, 2016 Table of Contents TABLE OF CONTENTS Abbreviations ................................................................................................................................. 1 Chapter One - General Summary .................................................................................. 3 1.1 Zusammenfassung ............................................................................................................................. 5 1.2 Summary ................................................................................................................................................ 7 Chapter Two - Introduction ........................................................................................... 9 PART I– Human Immune System ........................................................................................... 11 PART II– Natural Killer Cells ................................................................................................... 11 2.1 Receptors Shaping NK Cell Biology ......................................................................................... 13 2.1.1 Killer Immunoglobulin-like Receptors ............................................................................. 14 2.1.2 CD94–NKG2 heterodimer receptors and NKG2D ........................................................ 19 2.1.3 Natural cytotoxicity receptors ............................................................................................. 20 2.1.4 2B4, KLRG1 and co-stimulatory receptors ..................................................................... 21 2.2 Developmental stages of Natural Killer cells ...................................................................... 23 2.2.1 Early development of NK cell precursors ........................................................................ 24 2.2.2 Late stages of NK cell development: early vs. late differentiation ........................ 26 2.2.3 Immunological memory in innate immunity ................................................................. 28 2.3 Education and Disarming of NK cells ..................................................................................... 31 2.4 The NK cell immunological synapse ....................................................................................... 35 PART III – Dendritic Cells ......................................................................................................... 37 2.1 Dendritic cell subsets .................................................................................................................... 38 2.2 Cross-talk between DCs and NK cells ..................................................................................... 40 2.2.1 NK cell priming by DCs ............................................................................................................ 40 2.2.2 DC editing by NK cells .............................................................................................................. 41 PART IV – Epstein Barr Virus .................................................................................................. 41 2.1 EBV life cycle ..................................................................................................................................... 41 2.2 Immune response to EBV ............................................................................................................ 44 V Table of Contents 2.2.1 Innate .............................................................................................................................................. 44 2.2.2 adaptive ......................................................................................................................................... 45 PART V – Humanized Mice ...................................................................................................... 46 PART VI – Aim and Outline ...................................................................................................... 48 Chapter Three - Natural Killer Cell Repertoire Development and Education Under MHC Class I Influence in Trans ..................................................................... 49 Cognate HLA absence diminishes human NK cell education in trans ....................... 51 3.1 aBSTRACT ......................................................................................................................................... 52 3.2 INTRODUCTION ............................................................................................................................... 53 3.3 RESULTS ............................................................................................................................................. 56 3.3.1 a novel in vivo model with parallel reconstitution of two donors’ immune compartments in NSG mice .............................................................................................................. 56 3.3.2 Development of the KIR repertoire on NK cells is not influenced by the HLA haplotype in trans ................................................................................................................................. 58 3.3.3 EBV infection does not force skewing of the KIR repertoire on NK cells in huNSG mice .............................................................................................................................................. 60 3.3.4 absence of cognate HLa abrogates NK cell education in huNSG mice ................ 62 3.3.5 Non-educated NK cells still display inhibition in response to cognate HLa ..... 64 3.3.6 Mixed reconstituted huNSG mice display superior immune control towards EBV .............................................................................................................................................................. 66 3.3.7 NK cells mediate improved immune control of EBV infection in mixed reconstituted mice ................................................................................................................................ 68 3.4 DISCUSSION ...................................................................................................................................... 70 3.5 METHODS ........................................................................................................................................... 73 3.6 aUTHOR CONTRIBUTIONS ......................................................................................................... 76 3.7 aCKNOWLEDGMENTS .................................................................................................................. 76 3.8 SUPPLEMENTaL FIGURES .......................................................................................................... 77 3.9 SUPPLEMENTaL EXPERIMENTaL PROCEDURES…………………………………………...83 VI Table of Contents Chapter Four - Interaction of Natural Killer Cells with Plasmacytoid Dendritic Cells .................................................................................................................. 85 Human natural killer cells form activating synapses with plasmacytoid dendritic cells without killing them ......................................................................................................... 87 4.1 aBSTRaCT .......................................................................................................................................... 88 4.2 INTRODUCTION ............................................................................................................................... 89 4.3 RESULTS ............................................................................................................................................. 91 4.3.1 Human NK cells and pDCs form immunological synapses with polarization of actin and the type I IFN receptor in NK cells ............................................................................ 91 4.3.2 Interaction with pDCs leads to phenotypic activation of human NK cells ........ 95 4.3.3 pDCs increase NK cell cytotoxicity ..................................................................................... 97 4.3.4 pDCs are not killed by NK cells ............................................................................................ 99 4.4 CONCLUSIONS ............................................................................................................................... 101 4.5 MaTERIaL aND METHODS ..................................................................................................... 102 4.6 aCKNOWLEDGEMENTS ...........................................................................................................
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