Age-exacerbated bystander resident CD8+ T cell responses in pulmonary fibrotic sequelae of influenza 4161

Abstract Description distinct forms of long-COVID that can last more than three years, are associated with persistent activation of T cells. We and others demonstrated that CD8 T cells that respond to influenza infection can spontaneously cause pulmonary fibrosis lasting a lifetime in aged mice. This model recapitulates key features of epithelial and fibroblast dysplasia observed in patients that require lung transplant due to COVID-19 related pulmonary fibrosis. Our data suggests understanding what distinguishes age-associated pro-fibrotic from quiescent T cell responses in the lung, could aid rational development of alternative therapeutics. Here, using intravital cell compartment labeling and a functional high-dimensional flow cytometry screen, we identified a subset of parenchymal CD8 T cells with age-exacerbated responses to many cytokines sustained in aged mouse lungs three months after infection. Albeit much lower-grade, these indiscriminate bystander responses elicit CD8 T cell functions usually restricted by the required presence of their extremely specific foreign antigen. Our supporting data from independent models, suggest a potential role for steady-state, but not recruited alveolar macrophages in limiting bystander susceptibility in a subset of parenchymal CD8 T cells. Our data implicate cellular and molecular mechanisms that link age and early infection severity with long-term CD8 T cell-dependent fibrotic responses to pandemic-relevant respiratory viruses. Funding Sources American Lung Association Grant: ERP-1251983 Topic Categories Viral Immunology (VIR)