The role of the aging lung microenvironment in alveolar regenerative decline

Abstract

Old age is a primary risk factor for the incidence and severity of lung disease such as COPD, IPF, and ARDS, yet how aging contributes to diseases characterized by insufficient repair of the gas-exchange surface remains poorly understood. Alveolar type 2 (AT2) cells serve as a facultative progenitor for the gas-exchange surface, and their number and regenerative capacity are known to decline with age in tandem with prominent transcriptional changes. Aged AT2 cell decline almost certainly contributes to poor outcomes in age-related lung disease. AT2 cells experience some of the largest transcriptional changes during lung aging, but the contributions of the aged lung microenvironment to AT2 cell regenerative decline have not been thoroughly interrogated. Using aging mouse models, single-nucleus multiomic sequencing, and ex vivo organoid assays I identified a conserved upregulation of MHC-I mediated antigen presentation in aged AT2 cells, characteristic of a chronic interferon γ (IFNγ) response. I present evidence that elevated antigen presentation gene expression is dependent on the aged lung microenvironment, as it was lost in ex vivo organoid culture and was not encoded in altered chromatin accessibility in regulatory regions of these genes. IFNγ was sufficient to selectively repress alveolar organoid growth, and neutralization of IFNγ signaling in vivo partially restored aged AT2 cell regeneration. I further showed that elevated IFNγ in the aged lung originates from CD8+ T cells accumulating in spontaneous tertiary lymphoid structures (TLS) in the aged lung, theoretically creating a spatially organized gradient of chronic IFNγ exposure across the alveolar epithelium. These findings establish a model in which age-related accumulation of lung-resident T cells generates a local inflammatory niche that represses AT2 cell self-renewal independently of any overt injury. My results demonstrate that aged AT2 cells are more sensitive to subtle inflammatory processes in the local microenvironment than previously appreciated, and that targeting IFNγ signaling or age-related T cell accumulation represents a promising avenue for restoring alveolar regeneration and improving lung function in advanced age.