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Modulation of Naïve CD4+ T Cell Activation and Dendritic Cell Function MODULATION OF NAÏVE CD4+ T CELL ACTIVATION AND DENDRITIC CELL FUNCTION IN THE LUNGS DURING PULMONARY MYCOBACTERIAL INFECTION by MURSALIN M. ANIS Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Thesis Advisors: Dr. W. Henry Boom, M.D. Dr. Clifford V. Harding, M.D., Ph.D. Department of Pathology and Division of Infectious Diseases CASE WESTERN RESERVE UNIVERSITY August 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. DEDICATION For my mother and father TABLE OF CONTENTS Signature Sheet ii CWRU Waiver iii Dedication iv Table of Contents v List of Tables vii List of Figures viii Acknowledgements x List of Abbreviatioins xi Abstract xii Chapter 1: Introduction 1 Lung environment 2 Chemokines 3 MTB infection in the lungs 6 Adaptive immunity to MTB 6 Formation of tertiary lymphoid structures 8 Cytokines and T cell differentiation 11 Naïve and effector T cells 13 Biology of TCR gene rearrangement 14 TCR transgenic mice – a tool 16 Ag85B-specific TCR transgenic mouse 18 Chapter 2: Activation of naïve CD4+ T cells 20 during pulmonary mycobacterial infection Summary 21 Introduction 22 Materials and Methods 24 Results 32 Discussion 46 Chapter 3: Generation of a MTB-specific T cell receptor 52 transgenic mouse Summary 53 Introduction 54 Materials and Methods 55 Results 59 Discussion 70 Chapter 4: Modulation of pulmonary dendritic-cell function 72 during mycobacterial infection Summary 73 Introduction 74 Materials and Methods 75 Results 81 v Discussion 91 Chapter 5: Discussion 96 Notebook table 114 Works Cited 115 vi List of Tables 3.1 Sequence of primers used to identify and clone Vα and Vβ 56 segments of Ag85B-specific T cell receptor 5.1 List of the experiment numbers corresponding to the presented figures 114 vii List of Figures 1.1 GPCR signaling during chemotaxis of leukocyte 5 1.2 Architecture of secondary and tertiary lymphoid organs 10 1.3 Cytokines and T-cell differentiation 12 1.4 Gene rearrangements that yield a productive T cell receptor 15 2.1 BCG infection causes enrichment and accumulation of 33 OVA-specific T cells after airway OVA challenge 2.2 BCG infection enhances T cell activation in the lungs 35 2.3 Pulmonary infection increases the frequency of antigen-specific 37 T cells responding to an airway antigen 2.4 BCG infection induces OVA-specific T cell proliferation in the 39 lungs after airway OVA challenge 2.5 BCG infection increases accumulation of effector antigen-specific 41 T cells in the lungs after airway antigen challenge 2.6 Mycobacterial infection induces naïve OVA-specific T cells 43 to differentiate into Th1 effectors in response to airway OVA challenge 2.7 BCG infection causes up-regulation of MHC-II on lung 45 CD11c+ cells harboring intranasal Fluos-labeled OVA 3.1 Vβ surface expression on Ag85B reactive T cell hybridomas 60 3.2 Vα cloning scheme 62 3.3 BLAST search identifying Vα5 leader sequence 64 3.4 Colony PCR of genomic Vα and Vβ sequences of BB7 65 3.5 Vα5Jα30 and Vβ11DJβ2.1 sequences of BB7 TCR 66 3.6 Restriction digests of pTβ-Vβ colonies 68 3.7 Restriction digests of pTα-Vα colonies 69 viii 4.1 Accumulation and maturation of dendritic cells in the lung 82 during BCG infection 4.2 CCR7 mRNA and surface expression on lung DCs are not 84 increased during peak and late stages of BCG infection 4.3 BCG infection upregulates expression of CCL19 in lung in 86 a MyD88-dependent manner 4.4 BCG infection modulates CCR7-mediated chemotaxis of 88 lung DCs 4.5 BCG infection alters ability of lung CD11c+ cells to present 90 peptide to naïve CD4+ T cells in vitro 5.1 Activation of naïve CD4+ T cells by lung DCs 101 5.2 Chemokine receptor CCR7-signaling pathway 106 ix ACKNOWLEDGEMENTS My parents have always taught me to develop a deep respect for my teachers. I would like to thank all of my teachers who have motivated me to pursue a career in medicine and science. I am indebted to Mr. Joseph Tarello, Ms. Mary Sceppa, Dr. Andrew Souers and Dr. Peter Radkowski for their guidance and inspiration during high school and college. The work here would not be possible without the mentorship of Dr. W. Henry Boom and Dr. Clifford V. Harding. They had given me considerable freedom to explore and pursue topics in Immunology that interested me most. At critical junctures they have provided insights that transformed the nature of the research to one of understanding important biological phenomena. Henry’s encouragement always fought off despair. I would like to thank past and present members of Henry Boom’s Laboratory: Roxana Rojas, Scott Fulton, Scott Reba, David Canaday, Adam Gehring, Robert Mahon, Martha Torres, Jeremy Thomas, Leola Jones, Scott Mahan and Keith Chervenak. Due to our close collaboration with Cliff Harding’s I would like to thank members of his lab who have helped me tremendously: Nancy Nagy, Meghan Pennini, Yi Liu (for qRT-PCR studies), Nicole Pecora, Reginald Gray, Michael Drage, Aaron Tobian, Rish Pai, Peter Chefalo, Gareth Hardy, David Askew, and Lakshmi Ramachandra. I would also like to thank Melanie Campbell in Alan Levine’s lab and members of Eric Arts’ lab. Lastly, but most importantly I would like to acknowledge my mother and father; their love and prayers kept me company during long nights in the lab. I am grateful for my loving sisters, Rehnuma and Soniya and my dear wife Nasreen for their love and support. My brother in faith, Khalifah Alyy’s friendship and support kept me going. x ABBREVIATIONS Ab antibody Ag, antigen APC antigen presenting cell BALT bronchus-associated lymphoid tissue BCG bacillus Calmette Guérin BCG+OVA BCG-infected mice given OVA intranasally BLC B lymphocyte chemoattractant BMDC bone marrow-derived dendritic cells DC dendritic cells ELC EBV-induced molecule 1 ligand chemokine, CCL19, MIP3β G protein guanine nucleotide binding protein GeoMFI geometric mean fluorescent intensity GPCR G-protein coupled receptor mAb monoclonal antibody MHC major histocompatibility complex MTB Mycobacterium tuberculosis PAMP pathogen associated molecular pattern PCR polymerase chain reaction pOVA OVA peptide 323-339 a.a. SLC secondary lymphoid chemokine, CCL21 xi SLO secondary lymphoid organ TCR T cell receptor TLO tertiary lymphoid organ TLR Toll-like receptor xii Modulation of naïve CD4+ T cell activation and dendritic cell function in the lungs during pulmonary mycobacterial infection Abstract By MURSALIN M. ANIS Initiation of CD4+ T cell responses is critical for a successful host response against the intracellular pathogen Mycobacterium tuberculosis (MTB). Naïve CD4+ T cells are activated by dendritic cells (DCs) that sample antigen in the periphery, upregulate chemokine receptor CCR7, and migrate to secondary lymphoid organs to encounter naïve CD4+ T cells. Pulmonary mycobacterial infection with the attenuated strain, Mycobacterium bovis BCG is used as a model to study host immune responses in the lungs. During BCG infection, lung bacterial burden peaks 4-6 wks post-infection and declines to undetectable levels by 12-14 wks. Inflammation caused by peak BCG infection (4-6 wks) led to enhanced naïve CD4+ T cell responses directed against a model airway antigen, ovalbumin (OVA). BCG infection caused accumulation, activation, and proliferation of OVA-specific CD4+ T cells in lung and draining mediastinal lymph node (MLN). Compared to uninfected mice, infected mice had greater proliferation in lung and lymph node but only infected mice had detectable in situ proliferation of OVA-specific CD4+ T cells in the lungs. BCG-infection induced expression of CCL19 in the lungs; CCL19 is a CCR7 ligand and naïve T cell chemoattractant. Lung inflammation, during infection, caused accumulation xiii and maturation of lung DCs that could present peptide antigens ex vivo. OVA-specific CD4+ T cells from the lungs of infected mice were more likely to differentiate into effector T cells and produce IFN-γ than T cells from uninfected mice. BCG infection caused accumulation and maturation of DCs in infected lungs even as the mycobacterial burden declined. Lung DCs from infected mice expressed increased amounts of MHC-II but comparable amounts of CCR7 relative to uninfected mice. Gene expression of a CCR7 ligand, CCL19 progressively increased throughout BCG infection and the expression was MyD88-dependent. Lung CD11c+ cells from BCG-infected mice activated OVA-specific naïve CD4+ T cells more than lung CD11c+ cells from uninfected mice. Therefore, our findings suggest that during BCG infection, inflammation and sustained expression of CCL19 recruit and retain mature DCs in the lung where they can activate naïve CD4+ T cells. xiv CHAPTER 1 Introduction 1 Overview Ever since the emergence of HIV, the intracellular pathogen Mycobacterium tuberculosis (MTB) has come into the radar of concerned public health officials and researchers in the developed nations. Even in immunocompetent individuals MTB is rarely eradicated; rather, in the majority of cases MTB establishes a latent infection. Latently infected people have a life-time risk of 5-10% for developing pulmonary reactivation tuberculosis. CD4+ T-cell responses are critical in the host response to MTB. Dendritic cells (DCs) are regarded as the primary antigen presenting cells (APCs) responsible for activating naïve CD4+ T cells. Modulation of DC function could lead to diminished immunity to MTB and allow latent infection to develop (Flynn 2004; Marino, Pawar et al. 2004). Lung Environment As primary organ for gas exchange the lungs come into contact with both innocuous particulates and pathogens.
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