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Characterization of Human T-Bet-Expressing B Lymphocytes and Their Role in the Hiv Immune Response

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Characterization of Human T-Bet-Expressing B Lymphocytes and Their Role in the Hiv Immune Response University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Characterization Of Human T-Bet-Expressing B Lymphocytes And Their Role In The Hiv Immune Response James Knox University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Allergy and Immunology Commons, Cell Biology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Microbiology Commons Recommended Citation Knox, James, "Characterization Of Human T-Bet-Expressing B Lymphocytes And Their Role In The Hiv Immune Response" (2017). Publicly Accessible Penn Dissertations. 2742. https://repository.upenn.edu/edissertations/2742 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2742 For more information, please contact [email protected]. Characterization Of Human T-Bet-Expressing B Lymphocytes And Their Role In The Hiv Immune Response Abstract Humoral immunity is critical for the prevention and control of viral infections, yet the specific B cells and mechanisms regulating antiviral responses in humans remain poorly defined. The Th1-associated transcription factor T-bet coordinates intracellular pathogen immune responses, and recent murine studies identified a -bet-exprT essing B cell subset that mediates humoral antiviral immunity, but an analogous cell population has not been identified in humans. In this study, we sought to investigate the role of T-bet-expressing B cells during human viral infections. We identified -betT expression within the memory B cell compartment of healthy individuals and described a relationship between the transcription factor and IgG1 and IgG3, two antiviral antibody isotypes. The T-bet+ B cell population was comprised of two discrete subsets: T-bet low resting memory cells and a highly activated, transcriptionally distinct T-bet high subset displaying an atypical memory phenotype. The T-bet high cell population transiently expanded in blood following vaccination with yellow fever or vaccinia virus; however, these cells were induced and maintained at an elevated frequency by chronic HIV viremia and were associated with increased expression and secretion of IgG1 and IgG3. The HIV gp140-specific esponser was maintained almost entirely by T-bet+ memory B cells in both viremic and aviremic donors. Together, our findings identify -betT is a critical regulator of humoral antiviral immunity in humans and suggest T-bet+ B cells specifically mediate the humoral immune responses to live viral vaccines and HIV. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Michael R. Betts Keywords B cell, HIV, Viral immunology Subject Categories Allergy and Immunology | Cell Biology | Immunology and Infectious Disease | Medical Immunology | Microbiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2742 CHARACTERIZATION OF HUMAN T-BET-EXPRESSING B LYMPHOCYTES AND THEIR ROLE IN THE HIV IMMUNE RESPONSE James J. Knox A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2017 Supervisor of Dissertation _______________________ Michael R. Betts, Ph.D. Associate Professor of Microbiology Graduate Group Chairperson __________________________ Daniel S. Kessler, Ph.D., Associate Professor of Cell and Developmental Biology Dissertation Committee: Michael P. Cancro, Ph.D., Professor of Pathology and Laboratory Medicine E. John Wherry, Ph.D., Professor of Microbiology George M. Shaw, M.D., Ph.D., Professor of Medicine James A. Hoxie, M.D., Professor of Medicine M. Anthony Moody, M.D., Associate Professor of Pediatrics, Duke University School of Medicine DEDICATION I dedicate this dissertation to my parents, Jim and Marybeth, for instilling in my brothers and me the value of hard work and providing love and support for as long as I can remember. ii ACKNOWLEDGMENT I would like to thank Michael Betts for his mentorship and the past and present members of the Betts lab for their support over the years. I would also like to thank John Wherry, Michael Cancro, Tony Moody, Jim Hoxie, and George Shaw for many helpful committee meeting discussions and suggestions regarding this project. Lastly, I would like to specifically acknowledge the experimental help provided by Marcus Buggert, Susan Moir, Lela Kardava, Georgia Tomaras, Tony Moody, and Kelly Seaton; without their assistance, much of this work would not have been possible. iii ABSTRACT CHARACTERIZATION OF HUMAN T-BET-EXPRESSING B LYMPHOCYTES AND THEIR ROLE IN THE HIV IMMUNE RESPONSE James J. Knox Michael R. Betts Humoral immunity is critical for the prevention and control of viral infections, yet the specific B cells and mechanisms regulating antiviral responses in humans remain poorly defined. The Th1- associated transcription factor T-bet coordinates intracellular pathogen immune responses, and recent murine studies identified a T-bet-expressing B cell subset that mediates humoral antiviral immunity, but an analogous cell population has not been identified in humans. In this study, we sought to investigate the role of T-bet-expressing B cells during human viral infections. We identified T-bet expression within the memory B cell compartment of healthy individuals and described a relationship between the transcription factor and IgG1 and IgG3, two antiviral antibody isotypes. The T-bet+ B cell population was comprised of two discrete subsets: T-betlow resting memory cells and a highly activated, transcriptionally distinct T-bethigh subset displaying an atypical memory phenotype. The T-bethigh cell population transiently expanded in blood following vaccination with yellow fever or vaccinia virus; however, these cells were induced and maintained at an elevated frequency by chronic HIV viremia and were associated with increased expression and secretion of IgG1 and IgG3. The HIV gp140-specific response was maintained almost entirely by T-bet+ memory B cells in both viremic and aviremic donors. Together, our findings identify T-bet is a critical regulator of humoral antiviral immunity in humans and suggest T-bet+ B cells specifically mediate the humoral immune responses to live viral vaccines and HIV. iv TABLE OF CONTENTS Chapter 1: Introduction 1.1 B cells and immunological memory: an introduction 1 1.2 Generation of humoral immunity 2 1.3 Antibodies and their function 5 1.4 Memory B cells 9 1.5 The transcription factor T-bet 15 1.6 B cells and HIV infection 18 1.7 Thesis goals 22 Chapter 2: Identification and characterization of human T-bet-expressing B lymphocytes 2.1 Summary 24 2.2 Introduction 25 2.3 Results 27 2.4 Discussion 45 Chapter 3: T-bet-expressing B lymphocytes are induced by HIV infection and dominate the gp140-specific B cell response 3.1 Summary 48 3.2 Introduction 49 3.3 Results 50 3.4 Discussion 65 Chapter 4: Conclusions, implications, and future directions 69 Chapter 5: Materials and methods 81 Bibliography 88 v LIST OF FIGURES Figure 1: T-bet expression in peripheral blood lymphocytes and monocytes 28 Figure 2: T-bet expression in B cell subsets and by antibody isotype 29 Figure 3: T-bet expression in peripheral blood memory B cell subsets 31 Figure 4: Transcriptional and phenotypic analyses of T-bethighCD85jhigh cells and other B cell subsets 33 Figure 5: B cell subset distribution and T-bet expression in paired peripheral blood and thoracic duct samples 36 Figure 6: T-bet expression in iliac lymph nodes, mesenteric lymph nodes, tonsil, and spleen 38 Figure 7: Longitudinal T-bet+ B cell dynamics in yellow fever virus-vaccinated or vaccinia virus-vaccinated individuals 43 Figure 8: Longitudinal T-bet+ B cell dynamics in acutely HIV-infected individuals 51 Figure 9: T-bet expression in B cells and RNA transcript levels in T-bethighCD85jhigh cells during HIV infection 58 Figure 10: Antibody isotype expression levels, correlations with T-bet, and siRNA T-bet knockdown in B cells of progressors 60 Figure 11: gp140-specific memory B cell phenotypes and serum Ig isotypes 64 Figure 12: Model proposing the induction and differentiation of T-bet-expressing B cells by viral infections 72 vi LIST OF TABLES Table 1: Yellow fever virus and vaccinia virus vaccine recipients 41 Table 2: RV217 Early Capture HIV cohort 52 Table 3: University of Pennsylvania Center for AIDS Research donor samples 54 Table 4: University of California San Francisco SCOPE cohort 56 Table 5: Acute and chronic HIV samples from University of Toronto and University of Pennsylvania CFAR cohorts 61 vii CHAPTER 1 INTRODUCTION 1.1 B cells and immunological memory: an introduction B lymphocytes, or B cells, were first described as a separate lymphocyte lineage from T cells in 1965 by Cooper et al., named as such for their bursa-dependent, versus thymus- dependent, development in birds (1). A number of seminal studies established B cells as the mediators of humoral immunity that give rise to plasma cells and ultimately regulate the production of antibodies, soluble γ-globulin proteins that recognize pathogens (2). B cells and antibodies are necessary for successful immune responses to various viruses, bacteria, fungi, and parasites, mediating pathogen clearance directly by neutralization or in concert with the innate and adaptive immune systems (3). The ability to harness humoral immunity through vaccination stands as perhaps
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