Goplen, N.

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)

Abstract The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

Respiratory tissue resident–like CD8 + T cells are associated with chronic lung sequelae post-acute COVID-19.

Abstract CD8 T cells must integrate antigenic and inflammatory signals to differentiate into efficient effector and memory T cells able to protect us from infections. The mechanisms by which TCR signaling and proinflammatory cytokine receptor signaling cooperate in these processes are poorly defined. In this study, we show that IL-12 and other proinflammatory cytokines transduce signals through the TCR signalosome in a manner that requires Fyn activity and self-peptide–MHC (self-pMHC) interactions. This mechanism is crucial for CD8 innate T cell functions. Loss of Fyn activity or blockade of self-pMHC interactions severely impaired CD8 T cell IFN-γ and NKG2D expression, proliferation, and cytotoxicity upon cytokine-mediated bystander activation. Most importantly, in the absence of self-pMHC interactions, CD8 memory T cells fail to undergo bystander activation upon an unrelated infection. Thus, CD8 T cell bystander activation, although independent of cognate Ag, still requires self-pMHC and TCR signaling.