Identifying Mechanisms of Lung Tissue-Resident Memory CD8 T cell Decay Open Access

Abstract

Tissue-resident memory (TRM) CD8 T cells are critical for cellular protection against pathogens at barrier tissues, where they can rapidly recognize and respond to invading pathogens due to their localization at the site of pathogen entry. In the lung, we find that protection against heterologous influenza virus infection wanes over time. This waning suggests a reduction of memory CD8 T cells. TRM are known to be long-lived within the tissue, but we find this not the case in the lung. We find a loss of airway and interstitium TRM, two distinct lung resident subsets, occurs gradually over 6-8 months. This loss is not due to loss of specific phenotypic subsets, nor due to established TRM leaving the lung tissue as assessed using parabiosis experiments. We observed that airway and interstitium TRM are prone to apoptosis in the tissue. Using paired RNA and ATAC-seq, we find that flu-specific airway and interstitium TRM have distinct transcriptional and epigenetic profiles. The profile of airway TRM revealed activation of the amino acid stress response pathway. Restoration of nutrients to airway TRM revealed this pathway is reversible. Thus, the amino acid stress pathway plays a role in altering airway TRM survival, leading to gradual cell death under homeostatic conditions and possibly preventing subsequent damage that could occur through non- specific bystander activation.

Most tissue-resident T cell memory is examined in the context of a single infection and under homeostatic conditions. We examined how multiple infections impact pre-existing lung TRM. We found that parainfluenza virus infection induces a loss of influenza-specific cell-mediated protection against heterologous influenza challenge by driving the loss of pre-existing TRM. This loss of TRM was driven by local infection, but not by localized sterile inflammation or by competition for lung niches. Local infection in the lung drove release of significant extracellular ATP (eATP), known to induce cell death through the purinergic receptor P2RX7. Quenching of eATP using apyrase, which hydrolyzes ATP, prevented loss of TRM from the lung. Together, these data suggest that each subsequent lung infection reduces pre-existing cellular immunity by depleting lung TRM. Both the loss of airway resident TRM due to amino acid starvation, and the selective loss of non-specific TRM due to local infection, help define unique mechanisms of loss in lung TRM populations.

Table of Contents

Chapter I: Introduction.................................................................................1-56

Figures................................................................................................29-30

Fig. 1....................................................................................................29

Fig. 2....................................................................................................30

References.............................................................................................31-56

Chapter II: Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8 T cells ....... 57-117

Abstract...............................................................................................58

Introduction.......................................................................................... 59-61

Materials and Methods.............................................................................62-68

Results.................................................................................................69-80

Discussion.............................................................................................81-85

Acknowledgements and author contributions...................................86

Figures.............................................................................................87-100

Fig. 1................................................................................................87-88

Fig. 2................................................................................................89-90

Fig. 3................................................................................................91-92

Fig. 4................................................................................................93-94

Fig. 5................................................................................................95-96

Fig. 6................................................................................................97-98

Fig. 7...............................................................................................99-100

Supplemental Figures...................................................................101-107

Fig. S1.................................................................................................101

Fig. S2.................................................................................................102

Fig. S3...........................................................................................103-104

Fig. S4................................................................................................105

Fig. S5................................................................................................106

Fig. S6................................................................................................107

References..........................................................................................108-117

Chapter III: Unrelated respiratory infections compromise established cellular immunity by promoting loss of pre-existing lung-resident memory CD8 T cells ...118-153

Abstract.................................................................................................118

Introduction.......................................................................................120-122

Materials and Methods.........................................................................123-125

Results.............................................................................................126-130

Discussion..........................................................................................131-133

Acknowledgements and author contributions....................................134

Figures.............................................................................................135-142

Fig. 1.............................................................................................135-136

Fig. 2.............................................................................................137-138

Fig. 3.............................................................................................139-140

Fig. 4..................................................................................................141

Fig. 5..................................................................................................142

Supplemental Figures.......................................................................143-144

Fig. S1................................................................................................143

Fig. S2................................................................................................144

References..........................................................................................145-153

Chapter IV: Discussion........................................................................154-173

Fig. 1...................................................................................................164

References..........................................................................................165-173

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, General
Keyword	Influenza T cell Resident Memory Immunology
Committee Chair / Thesis Advisor	Jacob E. Kohlmeier, Emory University
Committee Members	Mehul S. Suthar, Emory University Rustom Antia, Emory University Lawrence H. Boise, Emory University Brian D. Evavold, Emory University

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