CD8 T cell Immunosurveillance of the Polyomavirus-Infected Central Nervous System Open Access

Frost, Elizabeth (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/1n79h4762?locale=en
Published

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

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

About this Dissertation

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
School
Department
Subfield / Discipline
Degree
Submission
Language
  • English
Research field
Keyword
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files