Unrelated respiratory infections promote the loss of pre-existing tissue resident influenza-specific memory CD8 T cells in the lung

Abstract

Abstract Tissue resident memory CD8 T cells mediate protective immunity at common sites of infection such as the skin, gut, female reproductive tract, and lung. Lung-resident memory T cells (lung TRM) have been found to be important for protective heterosubtypic immunity to influenza, however the efficacy of cellular immunity to influenza viruses wanes over time. Our data suggests this decline in protective immunity is due to the gradual loss of flu-specific lung TRM, which, in contrast to circulating flu-specific memory T cells and TRM in other tissues, steadily decrease in number for several months following primary infection. Notably, the loss of flu-specific lung TRM occurs throughout the TRM pool regardless of expression of the tissue residency markers CD69 and CD103. Furthermore, parabiosis experiments using influenza memory mice show that flu-specific lung TRM are not exiting the tissue, and thus the gradual loss of these cells is likely due to increased cell death compared to the systemic memory T cell pool. As the lung is continually exposed to environmental and biological insults that can result in localized inflammation, we sought to determine whether lung inflammation could promote the loss of pre-existing flu-specific lung TRM. Infection of influenza-immune mice with Sendai virus resulted in a significant decrease of the number of pre-existing flu-specific lung CD8 TRM compared to PBS controls. Importantly, Sendai infection had no impact on the number of systemic flu-specific memory CD8 T cells in the spleen. Together, these data show that lung inflammation induced by unrelated respiratory infections can promote the loss of pre-existing lung TRM and may explain the gradual loss of cellular immunity in the lung.