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Effect of NKG2C Absence on Natural Killer Cell Phenotype and Function in Human

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Effect of NKG2C Absence on Natural Killer Cell Phenotype and Function in Human Effect of NKG2C Absence on Natural Killer Cell Phenotype and Function in Human Immunodeficiency Virus/Cytomegalovirus Co-infection ©Emilie M. Comeau A thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Master of Science in Medicine Division of BioMedical Science Immunology and Infectious Diseases Faculty of Medicine, Memorial University of Newfoundland St. John’s, Newfoundland May 2018 Abstract Natural killer (NK) cells expressing NKG2C and CD57 expand following human cytomegalovirus (CMV) infection. This NK cell subset downregulates FcεR1γ and acquires enhanced capacity to mediate antibody-dependent cellular cytotoxicity (ADCC). Expansion of these differentiated NK cells is exaggerated in human immunodeficiency virus (HIV) infection. Individuals lacking the gene encoding NKG2C have diminished resistance to HIV, but it remains unclear whether differentiation into NK cells with superior ADCC is impaired in NKG2Cnull individuals. Therefore, our objective was to investigate if CMV-driven NK cell differentiation into enhanced killers is impaired in NKG2Cnull HIV-infected individuals. Phenotypic (CD57+, FcεR1γ-) and functional (IFN- γ, TNF-α induction and cytotoxicity) NK cell responses were compared between NKG2Cnull and matched NKG2C-expressing individuals by flow cytometry following stimulation through natural cytotoxicity receptors (using K562 cells) or CD16 (using monoclonal antibody, 3G8). Cytotoxicity was measured in 51Chromium release assays against anti-CD16-coated P815 cells (redirected lysis) and anti-human leukocyte antigen (HLA) class I antibody-coated C1R cells (classical ADCC). Antibodies were titrated to determine concentrations producing half maximal responses (EC50) to compare sensitivity. Our data indicate highly similar CMV-driven NK cell differentiation in terms of both general phenotype and function, regardless of NKG2C genotype. The observed equivalency between groups suggests alternate routes of CMV-driven NK cell differentiation, which are independent of NKG2C. ii Acknowledgments First and foremost I would like to thank my supervisor, Dr. Michael Grant, for his steady guidance, encouragement and patience. I feel extremely lucky to have landed under his supervision. I would also like to thank my supervisory committee, Drs. Sheila Drover and Rodney Russell, for their valuable feedback. My time spent in the Grant Lab would not have been nearly as enjoyable without the incredible support system it provided. I would like to thank Joey Heath for taking me under his wing and showing me the ropes, as well as Nick Newhook for generously sharing his project expertise. I would like to thank Neva Fudge and Krista Squires for their leadership as women in science, and Kayla Holder, whose endless drive and curiosity has inspired me to be more thorough in my pursuits. Finally, I would like to thank my parents for their tireless support. This research was supported in part by the Dean of Medicine‟s Fellowship and Memorial University of Newfoundland. iii Table of Contents Effect of NKG2C Absence on Natural Killer Cell Phenotype and Function in Human Immunodeficiency Virus/Cytomegalovirus Co-infection ............................................... i Abstract ..................................................................................................................... ii Acknowledgments ..................................................................................................... iii Table of Contents ...................................................................................................... iv List of Tables ............................................................................................................. vi List of Figures ........................................................................................................... vii List of Abbreviations and Symbols ........................................................................... viii Chapter 1: Introduction .......................................................................................... - 1 - 1.1 Natural Killer Cells ............................................................................................ - 1 - 1.1.2 Inhibitory NK Cell Receptors ...................................................................................... - 2 - 1.1.3 Activating NK Cell Receptors ...................................................................................... - 2 - 1.1.4 NK Cell-Mediated Killing ............................................................................................. - 5 - 1.1.5 Classical NK Cell Licensing .......................................................................................... - 7 - 1.1.6 NK Cell Stimulation Assays ......................................................................................... - 8 - 1.1.7 Pro-inflammatory cytokines ....................................................................................... - 9 - 1.2 Overview of Human Cytomegalovirus ................................................................... - 10 - 1.2.1 CMV & Adaptive Immunity....................................................................................... - 11 - 1.2.3 CMV & Innate Immunity ........................................................................................... - 12 - 1.2.4 Characterization of NKG2C+ NK Cells ....................................................................... - 14 - 1.2.5 Characterization of NKG2Cnull NK Cells ..................................................................... - 17 - 1.2.6 Epidemiology of CMV/HIV Co-infection ................................................................... - 20 - 1.3 Overview of Human Immunodeficiency Virus Infection ........................................ - 20 - 1.3.1 CMV/HIV Co-Infection .......................................................................................... - 21 - 2. Materials and methods ..................................................................................... - 24 - 2.1 Sample Collection and Peripheral Blood Mononuclear Cell Isolation ........................ - 24 - 2.2 Cryopreservation of PBMC ...................................................................................... - 26 - 2.3 Thawing PBMC ....................................................................................................... - 26 - 2.4 Identification of NKG2Cnull Individuals by Flow Cytometry ........................................ - 27 - 2.5 Confirmation of NKG2Cnull Genotype by Polymerase Chain Reaction ........................ - 27 - 2.5.1 Deoxyribonucleic Acid Isolation ............................................................................... - 27 - 2.5.2 NKG2C PCR ............................................................................................................... - 29 - 2.6 Matching NKG2Cnull Individuals to NKG2C-Expressing Control Group ........................ - 31 - 2.7 Flow Cytometry ...................................................................................................... - 31 - 2.8 NK Cell Stimulations ............................................................................................... - 33 - 2.9 Cytotoxicity Assays ................................................................................................. - 34 - 2.10 Statistical Analysis ................................................................................................ - 37 - 3. Results ............................................................................................................. - 39 - iv 3.1 Identification of NKG2Cnull subjects ......................................................................... - 39 - 3.1.1 Rationale .................................................................................................................. - 39 - 3.1.2 Identifying NKG2Cnull Individuals .............................................................................. - 39 - 3.1.3 Assigning an NKG2C-Expressing Matched Group ..................................................... - 41 - 3.2 Comparison of NK Cell Population Size and Phenotype between NKG2Cnull and NKG2C- Expressing Matched Groups ......................................................................................... - 46 - 3.2.1 Rationale .................................................................................................................. - 46 - 3.2.2 Comparison of Percent NK Cells within the Total Lymphocyte Population between Groups ............................................................................................................................... - 46 - 3.2.3 Comparison of FcεR1γ & CD57 Expression between Groups ................................... - 48 - 3.3 NK Cell Cytokine Responses to Stimulation (K562 and 3G8) ..................................... - 51 - 3.3.1 Rationale .................................................................................................................. - 51 - 3.3.2 NK Cell Cytokine Production in Response to NCR Stimulation (K562) ..................... - 52 - 3.3.3 NK Cell Cytokine Production in Response to CD16 Stimulation (3G8) ..................... - 52 - 3.4 Measuring NK Cell Cytotoxicity in Models of ADCC .......................................... - 53 - 3.4.1 Rationale .................................................................................................................. - 53 - 3.4.2 NK Cell Cytotoxicity against Antibody-Coated P815 and C1R
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