Factors impacting the generation and maintenance of CD8+ tissue-resident memory T cells following respiratory immunization Pubblico
Lobby, Jenna (Fall 2022)
Abstract
Despite the availability of a seasonal vaccine, influenza virus remains a critical burden to human health. The limited efficacy of current influenza vaccine strategies is largely due to the virus’ ability to evade established antibody responses. One potential strategy to achieving broad, long-lasting protection is to develop a T-cell based vaccine that recognizes conserved internal epitopes. While cellular immunity cannot prevent influenza infection, pre-existing antiviral T cells can limit viral replication and disease severity. Lung tissue-resident memory CD8+ T cells (CD8+ TRM) are a subset of memory T cells that remain localized within the lung tissue, where they provide rapid protection against viral challenge. However, CD8+ TRM in the lung gradually decline over time, correlating with a decline in cellular immunity to respiratory infection, including influenza. Currently, our knowledge of the mechanisms governing the maintenance of tissue-resident memory CD8+ T cells in the lung remains limited.
The data presented in this thesis identify mechanisms driving generation and maintenance of lung-resident CD8+ TRM in the context of two common vaccination strategies known to promote T cell immunity: recombinant adenovirus and live attenuated influenza vaccine (LAIV). Firstly, studies using adenovirus expressing influenza nucleoprotein (AdNP) have shown that NP antigen persists in immunized animals, resulting in protective CD8+ lung TRM being maintained long-term. Using a lineage tracing approach, we identify alveolar macrophages as the cellular source of persistent NP antigen in the lungs of AdNP-immunized mice. Importantly, depletion of alveolar macrophages following AdNP immunization results in significantly reduced numbers of NP+ CD8+ lung TRM.
LAIV elicits both humoral and cellular immune memory in children, but its efficacy is limited in adults. We hypothesized that pre-existing immunity from past infections and/or immunizations prevents LAIV from boosting or generating de novo CD8+ TRM. Using a series of mutated LAIV strains with varying capabilities of escaping pre-existing immunity, we determine that both pre-existing humoral and cellular immunity can limit the effectiveness of LAIV.
Combined, these studies identify several mechanisms that impact the generation and durability of cellular immunity in the lung. Together, the findings presented here will guide future cell-mediated vaccine strategies against respiratory pathogens.
Table of Contents
Table of Contents
CHAPTER I: INTRODUCTION 1
INFLUENZA & HUMAN HEALTH 1
Influenza virology 1
THE IMMUNE RESPONSE TO INFLUENZA VIRUS 4
Innate recognition of influenza infection 4
Dendritic cells and the initiation of the adaptive response 5
T cell response to influenza 6
T CELL MEMORY 9
Development of T cell memory during influenza A virus infection 10
CD8+ tissue-resident memory T cells 11
Techniques for identifying and studying TRM 12
Generation & maintenance of CD8+ TRM within the lung & airways 14
Effector functions of CD8+ TRM 18
CD8+ lung TRM and influenza infection 19
VACCINATION STRATEGIES AGAINST RESPIRATORY PATHOGENS 20
Current influenza vaccine strategy 20
Strategies to enhance TRM in the lung 21
Viral vectors as a vaccine platform for influenza 22
Impact of pre-existing immunity on TRM and vaccine efficacy 24
Summary 25
REFERENCES 27
CHAPTER II: PERSISTENT ANTIGEN HARBORED BY ALVEOLAR MACROPHAGES ENHANCES THE MAINTENANCE OF LUNG-RESIDENT MEMORY CD8+ T CELLS 73
ABSTRACT 74
INTRODUCTION 75
MATERIALS & METHODS 78
RESULTS 83
Figure 1 84
Figure 2 86
Figure 3 88
Figure S1 90
Figure 4 91
Figure S2 92
Figure 5 94
DISCUSSION 95
REFERENCES 100
CHAPTER III: BOTH HUMORAL AND CELLULAR IMMUNITY LIMIT THE ABILITY OF LIVE ATTENUATED INFLUENZA VACCINES TO PROMOTE T CELL RESPONSES 121
ABSTRACT 122
INTRODUCTION 123
MATERIALS & METHODS 125
Table 1 126
RESULTS 130
Figure 1 132
Figure 2 135
Figure S1 136
Figure S2 138
Figure 3 140
Figure 4 142
Figure S3 143
Figure 5 145
DISCUSSION 146
REFERENCES 150
CHAPTER IV: DISCUSSION 160
OVERALL IMPLICATIONS FOR VACCINE DESIGN 165
Location of antigen and TRM 165
Impact of prior (and future) infections & immunizations 167
TRM beyond respiratory infection 169
REFERENCES 171
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