Biology subjects

Trevail, R.

Publications and source records attributed to Trevail, R..

3 recordsLinked to original sources

bioRxiv2026

ITK Deficiency Attenuates Alveolar Hemorrhage by Enhancing Regulatory T Cell-Mediated Tissue Resilience

Pulmonary hemorrhage (PH) is a life-threatening manifestation of systemic autoimmunity caused by immune-mediated disruption of the alveolar capillary barrier. Despite high mortality, the molecular checkpoints that shift destructive inflammation toward protective immune regulation remain poorly defined. Here, using the pristane-induced PH model, we identify interleukin-2-inducible T cell kinase (ITK) as a critical regulator of autoimmune lung injury. ITK deficiency (ITK-/- ) conferred near-complete protection from PH and associated multiorgan injury, accompanied by reduced proinflammatory monocytes and neutrophils and increased Foxp3 regulatory T cells (Tregs). Adoptive transfer of ITK-/-; Tregs protected wild-type recipients from PH and suppressed systemic proinflammatory cytokines, identifying Tregs as key mediators of tissue protection. Mechanistically, lung ITK-/- ; Tregs exhibited increased amphiregulin, a mediator of tissue repair. Transcriptomic profiling further showed that ITK loss reprogrammed Tregs toward a metabolically and functionally enhanced state, with enrichment of oxidative phosphorylation, mTORC1 and STAT5 signaling, and tissue-repair programs. These findings establish ITK as a regulator of the balance between pulmonary injury and reparative immunity and support targeting the ITK axis in severe inflammatory lung disease.

immunology↗

bioRxiv2025

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

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.

immunology↗

bioRxiv2024

The scaffold protein CasL regulates T cell migration by restricting membrane blebbing

T cell migration into inflamed tissue is a key control point in the inflammatory response and relies on integrin interactions with their endothelial ligands. Here, we identify the signaling scaffold CasL (Hef1, NEDD9) as a central regulator of integrin-dependent migration in primary T cells. We found CasL is specifically needed for efficient migration on ICAM-1, but not VCAM-1 coated surfaces. While WT T cells migrating on ICAM-1 form an actin-rich cell front and move smoothly, T cells lacking CasL instead form numerous, aberrant membrane blebs. The abnormal blebbing observed in CasL KO T cells likely stems from diminished F-actin in the cell front coupled with increased contractile forces behind the nucleus, suggesting CasL regulates the cytoskeletal architecture in migrating T cells. Importantly, using an in vivo allogeneic hematopoietic transplant model we found that CasL promotes T cell migration into inflamed peripheral tissue, but was dispensable for trafficking to secondary lymphoid organs. Together, these results indicate CasL functions to control the balance of cytoskeletal components during integrin-dependent migration and highlight the importance of integrin signaling for proper migration into inflamed tissue.

cell biology↗