CD8 T cell Immunosurveillance of the Polyomavirus-Infected Central Nervous System 公开
Frost, Elizabeth (2016)
Abstract
Progressive multifocal leukoencephalopathy (PML) is a debilitating and often fatal demyelinating disease of the central nervous system (CNS) in immunosuppressed patients infected by the ubiquitous human JC polyomavirus (JCV). Demyelination is thought to result from lytically infected oligodendrocytes, which fail to be cleared in the setting of depressed JCV-specific T cell-mediated CNS surveillance, for example as a result of natalizumab therapy (targeting very late antigen-4 (VLA-4)-mediated T cell trafficking) for multiple sclerosis. Mechanisms of PML progression and CNS anti-viral immunity are poorly understood, largely due to lack of a tractable animal model resulting from restriction of polyomaviruses to co-evolved hosts. In recent years, humanized mouse models for infection with JCV have been developed but cannot offer insight into the interplay between host immune responses and viral infection. The aim of our work is to bridge this gap, utilizing intracerebral inoculation of immunocompetent mice with mouse polyomavirus (MPyV) to understand whether anti-viral CD8 T cells are protective against demyelinating disease. We show that MPyV productively replicates in the brain, establishing a low-level persistent infection despite robust VLA-4-independent recruitment of CD8 T cells, the majority of which are directed toward a single peptide epitope. These T cells do not undergo contraction. Instead, they are stably maintained independent of replenishment from the circulation or CD4 T cell-help. Brain- as well as kidney-resident memory T (TRM) cells retain high affinity T cell receptors, suggesting high antigen sensitivity is a trait of memory cells resident in multiple non-lymphoid organs and may be critical for protective pathogen-specific surveillance. MPyV-specific brain TRM cells sustain high levels of programmed cell death-1 (PD-1) receptor--regarded as a marker of T cell dysfunction resulting from chronic antigen stimulation--even as viral load declines. However, PD-1 does not prevent T cells from producing cytokines, controlling viral infection, or proliferating. Despite the presence of high-quality CD8 T cells, MPyV-infection induces CNS demyelination, which opposes what is currently accepted as the underlying cause of PML in humans. Our work raises important questions regarding present knowledge of PML pathogenesis and lays the foundation for an animal model of polyomavirus-induced CNS disease.
Table of Contents
CHAPTER 1: INTRODUCTION 1
1.1 Evidence that JCV-specific T cells confer protection from PML 8
1.2 CNS-resident memory CD8 T cells 10
1.3 The inhibitory PD-1 receptor balances immunity and immunopathology in the CNS 13
1.4 Using JCV to model PML in animals 15
1.5 JCV entry to the CNS 17
1.6 MPyV as a model to understand human polyomavirus pathogenesis 19
1.7 Summary 22
CHAPTER 2: RESIDENT-MEMORY CD8 T CELLS EXPRESS HIGH-AFFINITY T CELL RECEPTORS 23
Abstract 24
Introduction 25
Materials and Methods 26
Results and Discussion 29
Figures 36
CHAPTER 3: PD-1HI CD8 T CELLS IN THE BRAIN REMAIN FUNCTIONAL DURING PERSISTENT MPyV INFECTION 43
Abstract 44
Introduction 45
Materials and Methods 48
Results 52
Discussion 58
Figures 63
CHAPTER 4: MPyV INDUCES CNS DEMYELINATION AND RECRUITS CD8 T CELLS INDEPENDENT OF VLA-4 72
Abstract 73
Introduction 74
Materials and Methods 78
Results 82
Discussion 88
Figures 92
CHAPTER 5: DISCUSSION 103
REFERENCES 114
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