Lymphotoxin expressing lymphocytes regulates tissue injury in COPD pathogenesis

• Applicants: Thomas Mark Conlon, Ph.D.; Professor Dr. Hani Harb
• Subject Area: Immunology ; Pneumology, Thoracic Surgery
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570423984

COPD is an environmentally related progressive pulmonary disorder, presenting with largely irreversible airflow limitation, a result of chronic bronchitis and emphysema and still the third leading cause of death worldwide. It affects more than 400-600 million people globally, killing over 3 million people per year, with no curative therapy currently available. Cigarette smoke (CS) exposure induces a chronic inflammatory response composed of innate immune cells, predominantly neutrophils and macrophages, and T and B-lymphocytes of the adaptive arm. These immune cells infiltrating the COPD lung are organized into tertiary lymphoid structures called inducible bronchus-associated lymphoid tissue (iBALT), which are observed during lung tissue destruction (emphysema) in both humans and mice. iBALT formation requires the interaction of lymphotoxin β receptor (LTβR) on stromal organizer cells with TNF superfamily members lymphotoxin α (LTα) and β (LTβ), expressed by activated lymphocytes during chronic inflammation. Previously, we demonstrated that the blockade of lymphotoxin signalling not only resolved iBALT but also induced regeneration of lung tissue by re-activating endogenous WNT/β-catenin developmental pathways in alveolar epithelial cells and reversed disease progression. Crucially, we have shown that Notch4 expression on regulatory T-cells is very important for the pathogenesis of Asthma and lung viral infections including COVID19 infection. Moreover, our preliminary analysis has confirmed the upregulation of Notch4 expression on Treg cells in COPD patients as well as in a disease severity manner. In this study, we aim to elucidate the contribution of specific T cell subtypes as the primary source of LTβR ligand and its crosstalk with Notch4 in orchestrating tissue injury observed in the COPD lung by identifying 1) the T cell subtype crucial for LTα/β, LIGHT and Notch4 expression in both COPD patients and mice, 2) the crosstalk pathways upstream and downstream of Notch4- LTα/β, 3) using conditional T cell knock-out mice in COPD disease models and organoid models and finally 4) validate the lymphotoxin expressing cell subtype in COPD patients to delineate the contribution of LTα/β, LIGHT and Notch4 in disease progression. Thus, contributing to our long-term goal of targeting lymphocyte mediated lymphotoxin/Notch4 axis signalling as a novel therapeutic target to drive endogenous regenerative repair processes in COPD.

• DFG Programme: Research Grants