Respiratory viral infections from influenza and SARS-CoV-2—the novel coronavirus behind COVID-19—cause a disproportionally high number of deaths among elderly people. And older survivors are prone to long-term impairment of lung function. But the exact mechanisms regulating the development of chronic lung disease after viral pneumonia are unclear.
A new study offers one explanation for why older people may be more susceptible to lung inflammation and fibrosis following viral infection. By studying aged mice, Mayo Clinic researchers found that T cells that reside in tissues—as compared to circulating T cells—were defective after influenza infection. Rather than being protective, these T cells in old animals contributed to inflammation, according to findings published in Science Immunology.
The researchers argued that the discovery could help guide a T-cell-targeted treatment strategy for elderly patients with chronic lung disease after viral pneumonia, including COVID-19.
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The culprit T cells are called tissue-resident memory CD8+ T cells, or TRM cells. Instead of circulating in the body, they occupy tissues at portals where pathogens can enter, such as the skin, the lung and gastrointestinal tract. That's where they ramp up a response once they reencounter a pathogen that they have previously memorized.
In aged mice that survived an influenza A infection, the researchers noticed prolonged inflammation and tissue damage. They observed that tissue-infiltrating white blood cells like neutrophils and monocytes persisted in aged lungs much more so than they did in young mice. While young animals largely returned to a stable immune state, aged lungs retained elevated inflammation-related gene expression.
One observation drew the researchers’ attention: Aged lungs also expressed higher levels of genes related to the adaptive immune response, which is the branch of immune system that targets specific pathogens. There they found increased CD8+ memory T cells in the functional tissues of aged lungs. Further analysis confirmed that these T cells were bona fide TRM cells, and that there was very limited contribution from circulating memory T cells.
TRM cells are vital for defending against reinfection, so theoretically, excessive amounts of TRM should have correlated with enhanced protection against viral reinfection in mice. However, that was not the case.
Single-cell RNA sequencing revealed that these TRM cells lacked certain hallmarks of lung TRM in young mice. Post-infection aged lung TRM cells lost a critical subpopulation that helps mediate an immune response by releasing cytokines upon receiving certain stimuli, the team found.
To test whether the excessive accumulation of TRM cells indeed drives persistent inflammation and fibrosis in aged lungs, the researchers depleted the cells in aged mice. The lungs showed a marked reduction of inflammatory lesions, a significant drop in monocytes and neutrophils, and reduced fibrosis.
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While the study was done in influenza, the Mayo Clinic team believes their findings may inform researches in COVID-19. “Our work uncovers a cause of age-associated persistent inflammation and lung fibrosis following severe viral pneumonia, which may be germane to the current SARS-CoV-2 pandemic in which a portion of COVID-19 patients are experiencing chronic symptoms associated with long-lasting lung function impairment,” Jie Sun, the study’s corresponding author, said in a statement.
An earlier Nature Medicine study by a group of Chinese scientists suggested that pulmonary T cells from patients with COVID-19 are enriched with a TRM signature and CD8+ T cell expansion in the airways, the Mayo Clinic scientists noted in their study.
Memory CD8+ T cells have inspired ideas for directly fighting the novel coronavirus. By studying memory CD8+ T cells from recovered patients, a team led by TScan Therapeutics identified dominant targets of T cells during the natural immune response process, which the team argued could inform the development of vaccines, treatments and diagnostics.
In the future, the Mayo Clinic scientists intend to explore ways to restore the dysfunctional TRM cells’ protective roles and limit their inflammation-causing functions.