Impact of Respiratory Tract Resident Memory CD8 T Cells on Viral Transmission Restricted; Files Only
Michalets, Sarah E. (Fall 2024)
Abstract
Respiratory virus-specific T cells recognize internal, conserved viral epitopes, enabling protection against drifted and antigenically novel viral variants. One memory T cell subset, tissue resident memory T cells (TRM), remain within nonlymphoid tissues where they persist, poised to rapidly initiate effector functions upon exposure to their cognate antigen. Numerous studies have demonstrated that respiratory tract CD8 TRM can substantially reduce viral burdens upon heterosubtypic influenza virus infection and prevent immunopathology. However, these studies often rely upon intranasal challenge models where large viral doses are deposited uniformly throughout the respiratory tract. In nature, respiratory virus infection occurs by transmission; small numbers of virions deposit along the respiratory mucosa and replicate to form an initial foci of infection. Prior to the work presented in this thesis, it was unknown whether respiratory tract CD8 TRM were capable of preventing infection caused by natural respiratory virus transmission.
This thesis defines and characterizes the ability of respiratory tract CD8 TRM to protect against natural respiratory virus transmission. Using Sendai virus as a model of respiratory virus transmission, we show that antigen-specific CD8 TRM not only significantly reduce viral burdens upon breakthrough infection but can prevent detectable infection entirely, in correlation with the quantity of CD8 TRM in the respiratory tract. This protection elicited by CD8 TRM proved long lasting for at least six months upon intranasal immunization with a recombinant adenoviral vector vaccine. Furthermore, we evaluated the CD8 TRM effector mechanisms responsible for preventing viral transmission and learned that IFN-g signaling was essential. Rapid IFN-g secretion caused nasal cavity epithelial cells to adopt antiviral transcriptional states, increase antigen presentation, and secrete lymphocyte attractant chemokines. We assessed the respiratory tract localization of the CD8 TRM response to viral transmission and noted that TRM in the upper respiratory tract, but not lower respiratory tract, become activated, proliferate, and establish antiviral effector transcriptional programs in response to transmitted virus. Finally, we demonstrated that nasal cavity CD8 TRM alone are sufficient to protect against respiratory virus transmission.
The findings presented in this thesis provide critical insights for vaccine design aimed to prevent viral transmission and spread among populations.
Table of Contents
CHAPTER I: Introduction .......................................................................................................... 1
References ................................................................................................................................ 23
CHAPTER II: Tissue resident memory CD8 T cells provide durable protection against respiratory virus transmission through IFN-γ ................................................................ 61
Abstract .................................................................................................................................... 62
Introduction ............................................................................................................................. 63
Materials and Methods ........................................................................................................... 65
Results ...................................................................................................................................... 71
Discussion ................................................................................................................................. 77
Main Figures ............................................................................................................................ 81
Figure 1 .................................................................................................................................. 81
Figure 2 .................................................................................................................................. 83
Figure 3 .................................................................................................................................. 85
Supplementary Information ................................................................................................... 88
Extended Data Figure 1 ......................................................................................................... 88
Extended Data Figure 2 ......................................................................................................... 90
Extended Data Figure 3 ......................................................................................................... 91
Extended Data Figure 4 ......................................................................................................... 93
Extended Data Figure 5 ......................................................................................................... 94
Extended Data Figure 6 ......................................................................................................... 96
Extended Data Figure 7 ......................................................................................................... 97
Extended Data Figure 8 ......................................................................................................... 99
Acknowledgements & Author Contributions ..................................................................... 100
References .............................................................................................................................. 101
CHAPTER III: Vaccine-induced upper respiratory tract resident memory CD8 T cells are sufficient to inhibit productive infection after viral transmission ............................ 111
Abstract .................................................................................................................................. 112
Introduction ........................................................................................................................... 113
Materials and Methods ......................................................................................................... 115
Results .................................................................................................................................... 121
Discussion ............................................................................................................................. 1288
Main Figures .......................................................................................................................... 132
Figure 1 ................................................................................................................................ 132
Figure 2 ................................................................................................................................ 134
Figure 3 ................................................................................................................................ 136
Figure 4 ................................................................................................................................ 137
Supplementary Information ................................................................................................. 139
Extended Data Figure 1 ....................................................................................................... 139
Extended Data Figure 2 ....................................................................................................... 141
Extended Data Figure 3 ....................................................................................................... 142
Acknowledgements & Author Contributions ..................................................................... 143
References .............................................................................................................................. 144
CHAPTER IV: Discussion ....................................................................................................... 156
References .............................................................................................................................. 168
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