Imprinting of Lung-Resident T Cell Memory

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DESCRIPTION (provided by applicant): 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.