Bridging the Gap: The Emerging Role of memory CD8+ T Cells in Fibrotic Interstitial Lung Disease

Abstract

Interstitial lung disease (ILD) disproportionately affects older adults, yet the contribution of immunosenescence to disease pathogenesis remains poorly understood. In fibrotic ILDs (fILDs), CD8 + T cells accumulate in fibrotic regions, where they may drive disease by promoting cytotoxic inflammation, impairing epithelial repair, and sustaining senescence. CD8 + T cell exhaustion (CD8 + Tex) has also emerged as a hallmark of chronic lung disease, although its relationship to immunosenescence in ILD remains unclear. Here, we highlight the heterogeneity among CD8 + T cells in fILD, including effector- and senescent-like subsets, and identify programmed death (PD)-1 as a protective “brake” limiting tissue-damaging immunopathology. Functional profiling indicates that CD8 + T cells in fILD exhibit features consistent with ex-tissue-resident and effector memory CD8 + T cell subsets. Recent evidence from severe and post-acute viral injury demonstrates that PD-1hiCD8 + T cells balance protective immunity with restraint of fibrotic sequelae while also driving maladaptive epithelial remodeling through expansion of dysplastic basal-like cells and impaired alveolar regeneration. These observations suggest that CD8 + T cells in fILD may directly regulate the balance between tissue repair and fibrosis. Our recent studies have shown that the antifibrotic effects of pirfenidone and nintedanib may arise from selective modulation of profibrotic programs in CD8+/CD4 + T cells, lymphoid endothelial cells and dendritic cells. Collectively, these findings support a paradigm shift in which fILD reflects a dysregulation of local immune networks rather an inevitable consequence of aging. Most importantly, these networks are modifiable, offering opportunities for early detection, patient stratification, and stage-specific immunomodulatory interventions, with maladaptive memory CD8 + T cell functional states serving as potential biomarkers of disease susceptibility.