Innate Immune Responses to LCMV Armstrong and Clone 13 and Their Influence on the Development of Acquired Immunity Pubblico
Norris, Brian Andrew (2013)
Published
Abstract
Infection of mice with LCMV Armstrong (ARM) or Clone 13 (C13), results in acute and chronic infections respectively. However the early cellular and molecular mechanisms that mediate these disparate outcomes are poorly understood. We have characterized the innate immune responses that occur during acute and chronic LCMV infection, with a view to identifying early correlates and mechanisms of the later immune responses and viral loads. Two temporally distinct phases of innate immune response were observed: early DC responses during the first 72 hours of infection, and later myeloid cell expansion peaking at day 14 post infection.
During the first 72h of infection with ARM or C13, dendritic cells (DCs) upregulated activation markers, and produced innate cytokines independent of viral strain. CD8α+ and CD8α− DC populations decreased following activation, with CD8α+ DC nearly absent by 72h post infection. Finally, DCs and myeloid cells enriched during the first two days of ARM and C13 infection similarly stimulated OT-1 T cells in vitro.
In the second phase, by day 7, myeloid cells were expanded in
the spleen and the blood during both infections. However, while
myeloid cells contracted during ARM infection, C13 infection
increased and sustained high numbers myeloid cells, peaking at day
14. Ly6Chi monocytic cells expanded during C13 infection had the
morphology and phenotype of myeloid-derived suppressor cells (MDSC)
and potently suppressed T cell proliferation. Blocking iNOS or
IFN-γ abrogated the suppressive function of these cells.
CCR2−⁄− mice showed impaired mobilization of
myeloid cells during C13 infection, and had enhanced anti-viral T
cell function. By administering anti-Gr-1 antibody to C13 infected
mice we were able to temporarily deplete myeloid cells, leading to
increased cytokine production by LCMV-specific CD8+ T cells. Early
innate immune responses to ARM and C13 are indistinguishable by
classical methods of measuring activation and T cell stimulatory
function. However, during chronic infection myeloid cells become
massively expanded and are able to inhibit T cell proliferation and
function, contributing to viral persistence.
Table of Contents
TABLE OF CONTENTS ITEM PAGE DISTRIBUTION AGREEMENT I APPROVAL SHEET II ABSTRACT COVER III ABSTRACT IV COVER PAGE V ACKNOWLEDGEMENTS VI
TABLE OF CONTENTS VIII
LIST OF FIGURES XI LIST OF ABBREVIATIONS XIII CHAPTER 1: Introduction 1Part I: Innate Immune Receptors and Innate
Immune Cells 1Pattern Recognition Receptors (PRRs) and
Modulating Adaptive Immunity 1
Toll-like receptors (TLRs) 2 TLR adaptor molecules 2 TLR polarize adaptive responses 3 RIG-I like Receptors (RLRs) 4 NOD-like Receptors 5 Innate Immune Cells 6 Granulocytes 7 Natural Killer Lymphocytes 11 Macrophages 13 Dendritic cells 16 Monocytes 18Innate Cells During Chronic Inflammation:
Myeloid Derived Suppressor cells 20
Identifying MDSC 21 Expansion 21 Gaining Suppressive Function 22 Mechanism of suppression 23Part II: Lymphocytic Choriomeningitis Virus (LCMV)
as a Model for Acute and Chronic Viral Infections 26 Basic Virology of LCMV 26LCMV genome 27
Cellular Receptor aDG 27
Persistent LCMV strain Clone13 28
LCMV tropism 28
The Cellular Immune Response to LCMV 29CD8+ T cell mediated immunity 29
Memory subpopulations 30
CD4+ T cell responses 31
Anti-viral immune responses during
C13 infection 31
Molecular markers and characteristics
of exhaustion and immunosuppression 32
The Innate Immune Response to LCMV 34Innate responses to acute LCMV infection 34
Type I IFN and innate immune responses 35
References 38CHAPTER 2: Chronic, but not acute viral infections, induce
sustained expansion of myeloid suppressor cells that inhibitviral-specific T cell immunity 83
Summary 84 Introduction 85 Results 88 Discussion 103 Experimental Procedures 108 Acknowledgements 113 Figures 114 Figure Legends 125 References 132 CHAPTER 3: Summary, Discussion and Future Directions 140 Figures 151 Figure Legends 152 References 153About this Dissertation
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