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

AAbstract 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 beta catenin stabilization in T cells and its impact on PH. Using a novel transgenic mouse model (CAT Tg) with stabilized beta catenin, we demonstrate that beta-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 beta 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 beta-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 beta catenin agonist to mice with PH significantly attenuated disease severity. Our bioinformatic analysis confirmed that beta catenin stabilization upregulates pathways associated with tissue repair and immune homeostasis, including PI3K, Akt, angiogenesis, and STAT5 signaling. Collectively, these findings reveal that beta-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.