Terminally exhausted CD8⁺ T cells contribute to age-dependent severity of respiratory virus infection

Background: Lower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we hypothesized that severe respiratory illness in the elderly is due to deficient CD8⁺ T cell responses.

Results: Here, we establish an aged mouse model of human metapneumovirus infection (HMPV) wherein aged C57BL/6 mice exhibit worsened weight loss, clinical disease, lung pathology and delayed viral clearance compared to young adult mice. Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8⁺ T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8⁺ T cells into Rag1^-/- recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8⁺ T cells exhibit a terminally exhausted TCF1/7^- TOX⁺ EOMES⁺ phenotype. We confirmed similar terminal exhaustion of aged CD8⁺ T cells during influenza viral infection.

Conclusions: This study identifies terminal CD8⁺ T cell exhaustion as a mechanism of severe disease from respiratory viral infections in the elderly.