The lung is a common portal of pathogen entry, and respiratory pathogen such as influenza and Mycobacterium tuberculosis are major global health problems. Thus, a major challenge of pulmonary vaccinology is to develop an approach that will provide long-lasting and durable immunity in the lung. One approach to this problem is the development of vaccines designed to promote the generation of lung-resident T cell memory. In animal models and human studies, memory T cells have been shown to significantly reduce viral loads after influenza challenge, leading to faster viral clearance and decreased disease severity. A key finding from these and other studies was that the protective efficacy of memory T cells directly correlated with the number of memory T cells present in the lung at the time of influenza challenge; as the number memory T cells in the lung declined, so did protection from pathogen challenge. Therefore, generating memory T cells that reside in the lung parenchyma and lung airways is a promising strategy to enhance cellular immunty to influenza or other respiratory pathogens. However, we still lack a basic understanding of how to generate and maintain tissue-resident memory T cells at the site of infection (the lung) where they are uniquely positioned to rapidly respond to a respiratory infection. Furthermore, we do not know the effector mechanisms that lung resident-memory cells use to provide protecitive immuniy. To improve cellular immunity against respiratory pathogens we must first acquire a better understanding of the mechanism(s) that underlie the generation, maintenance, and recall of tissue-resident memory T cells in the lung airways and lung parenchyma. This is the goal of the current proposal.

Public Health Relevance

Respiratory infections, such as those mediated by influenza and Mycobacterium tuberculosis, constitute a major worldwide human health problem. One approach to enhance protective immunity against these pathogens is through the generation of memory T cells that permanently reside in the lung and are therefore uniquely positioned to provide immediate effector functions at the site of pathogen entry. The goal of the current proposal is to determine the mechanisms that imprint memory T cells to preferentially reside in the lung parenchyma and lung airways in order to better guide future cell-mediated vaccine design against respiratory pathogens.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Immunity and Host Defense (IHD)
Program Officer
Craig, Matt
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Emory University
Schools of Medicine
United States
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McMaster, Sean R; Wein, Alexander N; Dunbar, Paul R et al. (2018) Pulmonary antigen encounter regulates the establishment of tissue-resident CD8 memory T cells in the lung airways and parenchyma. Mucosal Immunol 11:1071-1078
Wein, Alexander N; Dunbar, Paul R; McMaster, Sean R et al. (2018) IL-36? Protects against Severe Influenza Infection by Promoting Lung Alveolar Macrophage Survival and Limiting Viral Replication. J Immunol 201:573-582
Barwick, Benjamin G; Scharer, Christopher D; Martinez, Ryan J et al. (2018) B cell activation and plasma cell differentiation are inhibited by de novo DNA methylation. Nat Commun 9:1900
Swaims-Kohlmeier, Alison; Haaland, Richard E; Haddad, Lisa B et al. (2016) Progesterone Levels Associate with a Novel Population of CCR5+CD38+ CD4 T Cells Resident in the Genital Mucosa with Lymphoid Trafficking Potential. J Immunol 197:368-76
Takamura, Shiki; Yagi, Hideki; Hakata, Yoshiyuki et al. (2016) Specific niches for lung-resident memory CD8+ T cells at the site of tissue regeneration enable CD69-independent maintenance. J Exp Med 213:3057-3073
Gilchuk, Pavlo; Hill, Timothy M; Guy, Clifford et al. (2016) A Distinct Lung-Interstitium-Resident Memory CD8(+) T Cell Subset Confers Enhanced Protection to Lower Respiratory Tract Infection. Cell Rep 16:1800-9
Zarnitsyna, Veronika I; Handel, Andreas; McMaster, Sean R et al. (2016) Mathematical Model Reveals the Role of Memory CD8 T Cell Populations in Recall Responses to Influenza. Front Immunol 7:165
McMaster, Sean R; Wilson, Jarad J; Wang, Hong et al. (2015) Airway-Resident Memory CD8 T Cells Provide Antigen-Specific Protection against Respiratory Virus Challenge through Rapid IFN-? Production. J Immunol 195:203-9