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Molecular Mechanisms of Human Γδ T Cell Activation and Tumor Cell Recognition

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Molecular Mechanisms of Human Γδ T Cell Activation and Tumor Cell Recognition UNIVERSIDADE DE LISBOA FACULDADE DE MEDICINA DE LISBOA MOLECULAR MECHANISMS OF HUMAN γδ T CELL ACTIVATION AND TUMOR CELL RECOGNITION Daniel Vargas Correia A dissertation submitted for the degree of Doctor of Philosophy in Biomedical Sciences, Specialization in Immunology 2011 UNIVERSIDADE DE LISBOA FACULDADE DE MEDICINA DE LISBOA MECANISMOS MOLECULARES DE ATIVAÇÃO DAS CÉLULAS T γδ HUMANAS NA SUA INTERAÇÃO COM CÉLULAS TUMORAIS Daniel Vargas Correia Tese orientada pelo Prof. Doutor Bruno Silva-Santos Doutoramento em Ciências Biomédicas, Especialidade de Imunologia 2011 Supervisor: Prof. Dr. Bruno Silva-Santos, Ph.D. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa. A presente dissertação foi realizada na Unidade de Imunologia Molecular do Instituto de Medicina Molecular, e foi apresentada à Faculdade de Medicina da Universidade de Lisboa, para obtenção do grau de Doutor em Imunologia. Todas as afirmações efetuadas no presente documento são da exclusiva responsabilidade do seu autor, não cabendo qualquer responsabilidade à Faculdade de Medicina de Lisboa pelos conteúdos nele apresentados. A impressão desta dissertação foi aprovada pela Comissão Coordenado- ra do Conselho Científico da Faculda- de de Medicina de Lisboa em reunião de 22 de Novembro de 2011. O trabalho aqui apresentado foi co- financiado pela European Molecular Biology Organization (EMBO), Fun- dação Calouste Gulbenkian (SDH- Oncologia 2008 - Projecto 99293) e Fundação para a Ciência e Tecnologia / FCT: PTDC/SAU-MII/71662/2006 ; PTDC/BIA-BCM/71663/2006 e bolsa de Doutoramento FCT-SFRH/BD/37898/ 07 Para os meus pais, Cesário e Filomena Somewhere, something incredible is waiting to be known. Carl Sagan TABLE OF CONTENTS ACKNOWLEDGEMENTS / AGRADECIMENTOS...............................................................xi ABBREVIATIONS......................................................................................................xv SUMÁRIO...............................................................................................................xix SUMMARY.............................................................................................................xxii 1. GENERAL INTRODUCTION.......................................................................1 1.1 T CELLS IN TUMOR SURVEILLANCE...................................................................... 1 1.1.1 The tumor immunosurveillance theory................................................ 1 1.1.2 The immune response against tumors ................................................ 2 1.1.3 The Cancer Immunoediting hypothesis ............................................... 3 1.1.3.1 Antigen recognition by T cells......................................................................3 1.1.3.2 T cell activation............................................................................................4 1.1.3.3 αβ T cell responses .....................................................................................6 1.1.4 Tumor antigens for αβ T cells............................................................... 7 1.1.5 αβ T cell-mediated cancer immunotherapy ......................................... 8 1.1.6 MHC class I-unrestricted tumor cell recognition................................. 9 1.2 NATURAL KILLER CELLS .................................................................................. 10 1.2.1 Natural Killer cell Inhibitory receptors ............................................... 11 1.2.1.1 Killer Ig-like receptors (KIRs).....................................................................12 1.2.1.2 CD94/NKG2A ............................................................................................12 1.2.2 Natural Killer cell Activating receptors .............................................. 15 1.2.2.1 Natural cytotoxicity receptors ....................................................................16 1.2.2.1.1 NKp30 .....................................................................................................16 1.2.2.1.2 NKp44 .....................................................................................................17 1.2.2.1.3 NKp46 .....................................................................................................18 1.2.2.2 NKG2D ......................................................................................................19 1.3 γδ T CELLS .................................................................................................... 20 1.3.1 γδ TCR repertoires................................................................................ 21 1.3.2 Ligand recognition by γδ T cells ......................................................... 22 1.3.3 Vδ1 T cells............................................................................................. 23 i 1.3.4 Vγ9Vδ2 T cells .......................................................................................24 1.3.5 Structure of the Vγ9Vδ2 TCR ...............................................................25 1.3.6 Ligands recognized by human Vγ9Vδ2 TCR.......................................26 1.3.6.1 Non-peptide ligands .................................................................................. 26 1.3.6.1.1 Phosphoantigens .................................................................................... 26 1.3.6.1.2 The isoprenoid biosynthetic pathways.................................................... 26 1.3.6.1.3 Aminobisphosphonates .......................................................................... 29 1.3.6.1.4 Alkylamines............................................................................................. 30 1.3.6.2 Peptide Ligands ........................................................................................ 31 1.3.6.2.1 Self- ligands ............................................................................................ 31 1.3.6.2.2 Non-self ligands ..................................................................................... 32 1.3.7 Vγ9Vδ2 T cell activation........................................................................33 1.3.8 Costimulation requirements of Vγ9Vδ2 T cells ..................................33 1.3.8.1 CD28......................................................................................................... 34 1.3.8.2 DNAM-1 .................................................................................................... 35 1.3.8.3 CD27......................................................................................................... 35 1.3.8.4 TOLL-like receptors................................................................................... 36 1.3.8.5 Fc Receptors: CD16.................................................................................. 37 1.3.8.6 Naturall Killer cell-inhibitory receptors (iNKRs) ......................................... 37 1.3.8.7 Natural Cytotoxicity Receptors: NKp44..................................................... 38 1.3.8.8 NKG2D...................................................................................................... 38 1.3.9 Tumor control by γδ T cells..................................................................39 1.3.9.1 Tumor cell recognition in vitro ................................................................... 39 1.3.9.2 Mouse tumor models................................................................................. 40 1.3.9.3 Clinical trials.............................................................................................. 41 1.4 OBJECTIVES OF THIS THESIS .............................................................................42 2. HIGHLY ACTIVE MICROBIAL PHOSPHOANTIGEN INDUCES RAPID YET SUSTAINED MEK/ERK- AND PI-3K/AKT-MEDIATED SIGNAL TRANSDUCTION IN ANTI-TUMOR HUMAN γδ T-CELLS ....... 43 2.1 ABSTRACT ......................................................................................................43 2.1.1 Background / Objectives.........................................................................43 2.1.2 Methodology/Principal Findings..............................................................43 2.2 INTRODUCTION.................................................................................................44 2.2.1 Phosphoantigen-mediated activation of Vγ9Vδ2 T cells .........................44 ii 2.3 MATERIAL AND METHODS ................................................................................ 46 2.3.1 In vitro cultures of human peripheral blood lymphocytes ....................... 46 2.3.2 Magnetic cell sorting and flow cytometry analysis.................................. 47 2.3.3 Cytometric Bead Array (CBA) ................................................................ 47 2.3.4 Protein isolation and phosphoimmunoblotting........................................ 47 2.3.5 RNA isolation and Affymetrix GeneChip analysis .................................. 48 2.3.6 Real-time quantitative PCR.................................................................... 48 2.3.7 Tumor cell cultures and in vitro killing assays ........................................ 49 2.3.8 Confocal microscopy.............................................................................. 49 2.3.9 Bioluminescent imaging of leukemia development in SCID mice........... 49 2.3.10 Statistical analysis.................................................................................. 50 2.4 RESULTS .......................................................................................................
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