# β-Catenin stabilization protects against alveolar hemorrhage through amphiregulin- and BATF-mediated Tregs

## TL;DR

This study shows that stabilizing β-catenin in T cells protects against deadly lung bleeding by boosting healing T cells and reducing inflammation.

## Contribution

The study reveals a novel protective role of β-catenin in T cells via amphiregulin and BATF-mediated Tregs in alveolar hemorrhage.

## Key findings

- β-catenin stabilization in T cells reduces lung injury and inflammation in a mouse model of alveolar hemorrhage.
- Adoptive transfer of β-catenin-stabilized Tregs provides protection against lung damage.
- Transcriptomic analysis shows enhanced tissue repair and immune homeostasis pathways in stabilized T cells.

## Abstract

Alveolar hemorrhage (AH) is a life-threatening condition with high mortality, yet the immunological mechanisms governing disease severity remain poorly defined. Here, we demonstrate a protective role for T cell–intrinsic β-catenin stabilization in AH using a transgenic mouse model (CAT-Tg) in which β-catenin is stabilized under the Lck promoter. We found β-catenin stabilization induced a distinct T cell phenotype marked by expansion of central effector memory cells (CD44+CD122+Eomes+T-bet+) and suppression of proinflammatory signaling, including reduced phosphorylation of STAT1, STAT3, and JAK1. Pristane-induced AH was attenuated in CAT-Tg mice, which exhibited reduced lung injury, decreased proteinuria, and diminished pulmonary proinflammatory cytokine production compared with WT controls. Protection was associated with a marked expansion of FOXP3+ Tregs. Mechanistically, β-catenin stabilization enhanced lung expression of amphiregulin and BATF, mediators of Treg stability and tissue repair. Adoptive transfer of CAT-Tg–derived Tregs into WT mice conferred superior protection against AH, reducing lung inflammation and proteinuria. Transcriptomic analyses revealed enrichment of tissue repair and immune homeostasis pathways, including PI3K-Akt, angiogenesis, and STAT5 signaling. Collectively, these findings identify β-catenin as a regulator of a protective amphiregulin/BATF/Treg axis, highlighting an immunomodulatory pathway with therapeutic potential for AH and inflammatory lung disease.

Our research identifies a new immune pathway that halts severe lung injury and promotes healing, offering potential therapeutic targets for fatal alveolar hemorrhage.