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Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1-Dependent Inhibition of T Cell Responses

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Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1-Dependent Inhibition of T Cell Responses CARCINOEMBRYONIC ANTIGEN-RELATED CELLULAR ADHESION MOLECULE 1-DEPENDENT INHIBITION OF T CELL RESPONSES by Hannah Sue-Wing Lee A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Molecular Genetics University of Toronto © Copyright by Hannah Sue-Wing Lee (2009) Carcinoembryonic Antigen-related Cellular Adhesion Molecule 1-Dependent Inhibition of T cell Responses Hannah Sue-Wing Lee Doctor of Philosophy, 2009 Department of Molecular Genetics University of Toronto ABSTRACT Neisseria gonorrhoeae infections are of major concern in areas of low socioeconomic status in both developed and developing nations. N. gonorrhoeae colonizes the genital tract by adhering to mucosal tissues through a number of adhesins, including the colony opacity-associated (Opa) proteins. Despite the random phase-variable expression of Opa proteins, 95% of clinical isolates express Opa variants that bind to the carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1), suggesting an essential role in vivo. Interestingly, even though gonorrhea is characterized by an intense inflammatory response, the organism is capable of evading the adaptive immune response. In previous studies by the Gray-Owen group, it has been established that certain gonococcal Opa variants bind CEACAM1 expressed by CD4+ T helper lymphocytes and, thereby, reduce their activation and proliferation. Since T cells are essential in establishing immune memory, inhibition of T cell function could explain the deficit in immune memory following gonococcal infection. In this thesis, I describe my studies to elucidate how CEACAM1 inhibits T cell activation on a molecular level. In Chapter 2, I demonstrate that outer membrane vesicles (OMVs) naturally shed by OpaCEA-expressing Neisseria sp. effectively inhibit CD4+ T cell activation, implicating a role for OMVs during infection and establishing that the Opa proteins do not have to be expressed in the context of the bacterium in order to elicit an inhibitory effect. In Chapter 3, I describe early steps in the CEACAM1-dependent inhibitory signaling cascade elicited when N. gonorrhoeae binds to CD4+ T cells. Finally, in Chapter 4, I show that a dynamic monomer-dimer equilibrium controls CEACAM1 function in epithelial cells and lymphocytes. Combined, the results presented in this thesis allow the derivation of a model to explain how CEACAM1 controls CD4+ T cell function at a molecular level. ii ACKNOWLEDGEMENTS This work is made possible by the contributions of many people who have helped, mentored, and supported me over the past several years. First and foremost, thank you to my supervisor, Dr. Scott Gray-Owen, for the opportunity to work in his lab. I appreciate his infectious excitement and passion for all things science. As well, I would especially like to thank him for providing the essential support and guidance throughout the course of my graduate studies that has made me into the scientist and person that I am today. I am indebted to Dr. Ian Boulton for his contributions to this work. It was a priviledge to have been exposed to his expertise and skills during my early stages of graduate school. I am also grateful to the past and present members of the Gray-Owen lab for being supportive of me during the highs and lows of graduate school. Thank you for the intellectual stimulation, hilarious conversations, and the many memorable experimental “situations” in the lab. It has been a true pleasure to work with them. Thank you to Dr. Tania Watts and Dr. Jeremy Mogridge for scientifically stimulating me. Their advice and suggestions have helped guide the science found in these pages. My many thanks and love goes out to all my friends and family. A special thanks to my parents, Elsa and Tim, for listening to my frustrations and celebrating my achievements. Thank you to my sister, Sophie, for the constant encouragement and love. Finally, I want to thank Byron for offering me perspective and balance through his companionship, intelligence, and steadfast support. iii TABLE OF CONTENTS ABSTRACT……………………………………………………………...........................………ii ACKNOWLEDGEMENTS……………………………….……………………………………iii TABLE OF CONTENTS ............................................................................................................ iv LIST OF FIGURES AND TABLES ........................................................................................... ix LIST OF ABBREVIATIONS ..................................................................................................... xi 1 INTRODUCTION .................................................................................................................... 1 1.1 The Pathogenic Neisseria ................................................................................................... 1 1.1.1 Neisseria gonorrhoeae ............................................................................................ 1 1.1.2 Neisseria meningitidis ............................................................................................. 2 1.1.3 Neisserial infection ................................................................................................. 2 1.1.4 Immune response to Neisseria ................................................................................ 4 1.1.5 Neisserial Opa proteins ........................................................................................... 6 1.2 Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) ................ 7 1.2.1 CEACAM1 structure .............................................................................................. 8 1.2.2 CEACAM1 lateral/apical localization .................................................................... 8 1.2.3 CEACAM1 uptake and recycling ......................................................................... 10 1.2.4 CEACAM1 phosphorylation and signaling .......................................................... 11 1.2.5 CEACAM1 dimerization ...................................................................................... 12 1.2.6 CEACAM1 function ............................................................................................. 15 1.2.7 CEACAM1 and the immune response .................................................................. 21 1.3 Mediation of T cell function by co-inhibitory receptors ................................................... 22 1.3.1 Co-inhibitory receptor cell surface expression ..................................................... 25 1.3.2 Phosphatase associations ...................................................................................... 26 1.3.3 Coinhibitory receptor coaggregation with activating receptors ............................ 28 iv 1.3.4 Dephosphorylation of substrates mediated by coinhibitory receptors .................. 28 1.3.5 Coimmunoreceptor dimerization regulates T cell responses ................................ 28 1.4 Thesis Objectives .............................................................................................................. 29 2 NEISSERIAL OUTER MEMBRANE VESICLES BIND THE CO-INHIBITORY + RECEPTOR CEACAM1 AND SUPPRESS CD4 T LYMPHOCYTE FUNCTION ..... 31 2.1 Abstract ............................................................................................................................. 31 2.2 Introduction ....................................................................................................................... 32 2.3 Results ............................................................................................................................... 33 2.3.1 Opa protein function in the context of OMVs ...................................................... 33 2.3.2 Meningococcal OMVs inhibit T cell proliferation ............................................... 34 2.3.3 CEACAM1 binding Opa proteins confer the lymphocyte inhibitory effect ......... 37 2.4 Discussion ......................................................................................................................... 37 2.5 Materials and Methods ...................................................................................................... 40 2.5.1 Cell lines and tissue culture techniques ................................................................ 40 2.5.2 Bacterial strains ..................................................................................................... 41 2.5.3 Preparation and physical characterization of OMVs ............................................ 41 2.5.4 Construction and expression of CEACAM1-Fc fusion proteins .......................... 42 2.5.5 Determination of Opa binding function ................................................................ 43 2.5.6 Flow cytometric analyses ...................................................................................... 43 2.5.7 Analysis of lymphocyte proliferation ................................................................... 44 3 CEACAM1 DYNAMICS DURING NEISSERIA GONORRHOEAE SUPPRESSION OF + CD4 T LYMPHOCYTE ACTIVATION ............................................................................ 45 3.1 Abstract ............................................................................................................................. 45 3.2 Introduction ....................................................................................................................... 46 3.3 Results ..............................................................................................................................
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