Cellular stress mediated by the local microenvironment regulates the homeostatic loss of tissue-resident memory CD8 T cells in different compartments of the lung

Abstract

Abstract Lung-resident memory T cells (lung TRM) are important for protective heterosubtypic immunity against influenza viruses; however, the efficacy of this cellular immunity wanes over time. To better understand the mechanisms leading to the decline of protective cellular immunity, we investigated the long-term maintenance of airway and parenchyma lung TRM. In contrast to circulating flu-specific memory T cells and TRM in other tissues, lung TRM numbers in the airways and parenchyma steadily decline for several months following influenza infection. All flu-specific lung TRM decline at similar rates regardless of expression of the tissue residency markers CD69 and CD103. Parabiosis experiments demonstrate that established lung TRM in the airways or parenchyma do not freely interchange with circulating memory T cells. Thus the gradual loss of these cells is likely due to increased cell death in the tissue. In support of this, airway and parenchyma lung TRM show increased apoptosis compared to systemic flu-specific memory T cells during homeostasis. To identify epigenetic and transcriptional programs specific to lung TRM, we performed parallel RNA-seq and ATAC-seq on flu-specific memory CD8 T cells from the airways, lung parenchyma, and spleen. We found that lung TRM populations have increased expression of genes associated with cellular stress, and airway TRM in particular have a signature associated with amino acid starvation and ER stress. Finally, intratracheal transfer experiments determined that the airway environment was sufficient to program the lung TRM transcriptional signature. Together, these data show that the decline of lung TRM is a direct result of cellular stresses driven by the lung microenvironment.