Identifying the Functional Role of Regulatory T Cell on Alveolar Stem Cell Niche during Lung Tissue Regeneration and Pulmonary Fibrosis

Abstract

Regulatory T cells (Tregs) play a critical role in modulating inflammation, repair, and fibrosis in lung injury. Using both acute and chronic lung injury models induced by intratracheal bleomycin, we investigated Treg dynamics and their impact on tissue regeneration and fibrosis. In acute lung injury, Tregs (CD4+ Foxp3+ cells) transiently increased during the inflammatory phase and declined during recovery, primarily localizing to tertiary lymphoid structures (TLS). Despite their abundance in TLS, direct interactions between Tregs and alveolar stem cells (AT2 cells) were rare, suggesting a predominantly indirect role in regeneration. In chronic lung injury, Tregs persisted in fibrotic regions, with increased localization to TLS and limited presence in alveolar areas. Using Foxp3-cre;tdTomato and Foxp3iDTR mouse models, we showed that Tregs recruited during inflammation could persist in the tissue when repair was incomplete. Depletion of Tregs exacerbated fibrosis, disrupted alveolar repair, and reduced AT2 cell numbers, highlighting their critical role in maintaining tissue homeostasis. These findings suggest that the dynamics of Tregs are driven by the local microenvironment, with reparative and fibrotic conditions influencing their function and persistence. Persistent Tregs in fibrotic areas may lose their reparative functions or acquire pathological characteristics, contributing to chronic injury. Understanding these dynamics is essential for developing therapeutic strategies targeting Tregs to promote lung repair and mitigate fibrosis.