β-Catenin Stabilization Protects Against Pulmonary Hemorrhage Through Amphiregulin and BATF- Mediated Regulatory T Cells

Abstract Pulmonary hemorrhaging (PH) is a life-threatening condition with a high mortality rate, yet the role of immune cells in its pathogenesis remains poorly defined. Here, we investigated the protective function of β-catenin stabilization in T cells and its impact on PH. Using a novel transgenic mouse model (CAT-Tg) with stabilized β-catenin, we demonstrate that β-catenin stabilization induces a distinct T-cell phenotype characterized by an expansion of central effector memory cells (CD44⁺, CD122⁺, Eomes⁺, T-bet⁺). Mechanistically, this effect was associated with suppression of key proinflammatory pathways, including reduced phosphorylation of STAT1, STAT3, and JAK1. PH was induced using pristane, and CAT-Tg mice were significantly protected from lung damage, showing reduced proteinuria and decreased pulmonary proinflammatory cytokine production compared with wild-type (WT) and T cell–specific β-catenin knockout (cKO) mice. This protection correlated with a marked increase in FOXP3⁺ regulatory T cells (Tregs) in CAT-Tg mice. We further identified a novel mechanism in which β-catenin stabilization enhances lung expression of Amphiregulin and BATF, two molecules essential for Treg function and tissue repair. Adoptive transfer of CAT-Tg Tregs into WT mice with pristane-induced PH conferred superior protection, as evidenced by reduced lung inflammation and proteinuria. The systemic administration of a β-catenin agonist to mice with PH significantly attenuated disease severity. Our bioinformatic analysis confirmed that β-catenin stabilization upregulates pathways associated with tissue repair and immune homeostasis, including PI3K-Akt, angiogenesis, and STAT5 signaling. Collectively, these findings reveal that β-catenin stabilization protects against pulmonary hemorrhage by inducing a specialized T-cell phenotype and establishing a protective Amphiregulin–BATF–Treg axis. This study identifies a novel immunomodulatory pathway with therapeutic potential for PH and other inflammatory lung diseases.