Factors that regulate and maintain CD8 T cell memory in the lung & airways Open Access

Abstract

Respiratory virus infections are a significant source of annual morbidity and mortality, constituting a major human health problem worldwide. Memory T cell responses are critical for quickly limiting viral replication and mitigating unnecessary inflammation responsible for immunopathology. Acting as sentinels capable of quickly organizing a secondary immune response upon pathogen challenge, resident memory CD8 T (TRM) populations are initially primed by microenvironment cues and antigen presenting cell (APC) licensing following acute infection of peripheral tissues. Despite their capacity for heterologous protection against influenza virus challenge, scant knowledge exists as to factors necessary to establish and maintain airway and lung parenchymal (LP) CD8 TRM cells. This body of work focuses on 1) the regulation of CD8 TRM cell establishment and maintenance in the LP and airways and 2) the protection conveyed by airway and LP CD8 TRM cells. In the absence of antibody protection, antigen-specific T cell responses, generated following previous influenza virus infection, reduce murine morbidity and mortality during lethal H7N9 influenza virus challenge. Airway CD8 TRM cells are alone sufficient to mediate protection upon heterologous challenge, working in concert with LP CD8 TRM cells to produce effector cytokines and kill infected cells, respectively. Furthermore, this work demonstrates that, in contrast to mechanisms described for other tissues, lung CD8 TRM cell establishment requires cognate antigen recognition once systemic effector T cells are recruited to the lung by local inflammation. Priming with local antigen and inflammation or native intranasal infection conveys equal protection upon heterologous challenge, while priming with local inflammation alone does not confer protection. This combination of local antigen and inflammation formed long-lasting TRM populations in the LP and airways that highly express the chemokine receptor CXCR6 and adhesion molecule CD49a, which uniquely characterize these two populations. Importantly, we demonstrate that CXCR6 is necessary for robust formation of virus-specific airway and LP CD8 TRM cells. These findings have identified novel mechanisms regulating the establishment and protective efficacy of lung CD8 TRM populations. Applying these findings may aid in the development of a new vaccination strategy for enhanced CD8 TRM cell establishment and protection.

Table of Contents

Chapter 1 ……………………………………………………..............1

Introduction: Evolving the Understanding of T Cell Memory

Table 1 …………………………………………………….…...............3

Table 2 ………………………………………………………….............5

Chapter 2 …………………………………………………….............41

Memory T cells generated by prior exposure to influenza cross react with the novel H7N9 influenza virus and confer protective heterosubtypic immunity

Table 1 ………………………………………………………...............45

Table 2 …………………………………………………………………..46

Figure 1 ………………………………………………………………… 48

Figure 2 ………………………………………………………………… 49

Figure 3 ………………………………………………………………… 51

Figure 4 ………………………………………………………………… 52

Chapter 3 ………………………………………………………………58

Airway-Resident Memory CD8 T cells Provide Antigen-Specific Protection against Respiratory Virus Challenge through Rapid IFN-γ Production

Figure 1 ………………………………………………………………… 64

Figure 2 ………………………………………………………………… 65

Figure 3 ………………………………………………………………… 65

Figure 4 ………………………………………………………………… 66

Figure 5 ………………………………………………………………… 67

Figure 6 ………………………………………………………………… 68

Figure 7 ………………………………………………………………… 69

Figure 8 ………………………………………………………………… 71

Chapter 4 ………………………………………………………………81

CXCR6 and CD49a co-expression promote airway and lung parenchymal resident memory CD8 T cell establishment following local antigen exposure

Figure 1 ………………………………………………………………… 87

Figure 2 ………………………………………………………………… 89

Figure 3 ………………………………………………………………… 91

Figure 4 ………………………………………………………………… 92

Figure 5 ………………………………………………………………… 94

Figure 6 ………………………………………………………………… 96

Figure 7 ………………………………………………………………… 97

Figure 8 …………………………………………………………………101

Chapter 5 ……………………………………………………………...106

Synthesis: Final Perspective, Extrapolative Implications & Future of Respiratory Pathogen Protection

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology Biology, Virology Biology, Microbiology
Keyword	Lung Respiratory Pathogen IFN-gamma Influenza virus Resident Memory T cells Lung airway Lung Parenchyma CXCR6 CD8 T cells Vaccination Heterologous Protection H7N9
Committee Chair / Thesis Advisor	Kohlmeier, Jacob, Emory University
Committee Members	Evavold, Brian, Emory University Moore, Martin L, Emory University Denning, Tim, Georgia State University Waller, Edmund K, Emory University

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