Unrelated respiratory infections compromise established cellular immunity by promoting apoptosis of pre-existing lung-resident memory CD8 T cells

Abstract

Abstract Lung-resident memory T cells (lung TRM) are critical for protective heterosubtypic immunity against influenza viruses. However, the efficacy of cellular immunity against respiratory pathogens such as influenza wanes over time due to the gradual loss of flu-specific lung TRM. One possible mechanism for this decline is frequent exposure to environmental and biological insults resulting in localized inflammation that promotes the death of established lung TRM. We investigated whether unrelated infections could exacerbate the loss of pre-existing, flu-specific lung TRM and reduce the efficacy of cellular immunity to subsequent influenza challenge. Infection of influenza-immune mice with Sendai virus, an unrelated murine parainfluenza virus, resulted in significantly higher viral titers and greater morbidity following influenza challenge compared to PBS-treated controls. This loss of protective cellular immunity corresponded to a significant decrease in the number of pre-existing flu-specific lung CD8 TRM compared to PBS controls due to increased apoptosis. This loss of pre-existing lung TRM following Sendai infection was not due to competition for limited resources or tissue niches between flu- and Sendai-specific lung TRM. Sendai infection had no impact on the number of systemic flu-specific memory CD8 T cells in the spleen. The loss of lung TRM required a respiratory infection, as LCMV infection and intranasal delivery of TLR agonists did not significantly reduce the number of pre-existing flu-specific lung CD8 TRM. Together, these data suggest that tissue damage induced by unrelated respiratory infections can promote the loss of pre-existing lung TRM and compromise cellular immunity against respiratory pathogens.