Factors impacting the generation and maintenance of CD8+ tissue-resident memory T cells following respiratory immunization 公开

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

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Virology Health Sciences, Immunology
关键词	Immunization Memory T cell Influenza
Committee Chair / Thesis Advisor	Jacob Kohlmeier, PhD, Emory University
Committee Members	Anice Lowen, PhD, Emory University Luisa Cervantes Barragan, PhD, Emory University Frances Eun-Hyung Lee, MD, Emory University Jeremy Boss, PhD, Emory University

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