Environmental induction of senescence-associated CD4+T cells that drive the formation of tertiary lymphoid organs in chronic lung disease

Chronic obstructive pulmonary disease (COPD) represents a major global health concern with rising prevalence and limited treatment options available. Central features of COPD are alveolar damage, chronic bronchitis and the formation of so-called inducible bronchus-associated lymphoid tissue (iBALT), which consists of B cell follicles surrounded by T cells zones. We have revealed that disruption of iBALT structures has been linked to improved disease outcomes measured by reduced emphysema development (Conlon et al., 2020). Thus, highlighting the important role of the adaptive immune system in the pathogenesis of chronic lung diseases. Whereby, the specific contribution of CD4 + T cells requires further elucidation. Interestingly in mice, aging can be linked to an increased population of PD-1 + CD44 high CD4 + T cells, including the specific subset of CD153 + PD-1 + CD4 + T cells which show characteristic features of cellular senescence and were termed senescence-associated T cells (SA T cells). Analysis of single-cell RNA sequencing data of lungs from COPD patients by us, further revealed an elevated expression of the combined features of SA T cells in COPD compared to control lungs. Furthermore, preliminary data from flow cytometry analysis of the presence of SA T cells in the lungs of mice subjected to a western diet for 2 months revealed a marked increase in PD-1 and CD153 expression among CD44 + CD4 + T cells in comparison to mice fed a normal diet. Therefore, we hypothesize that environmental factors, such as cigarette smoke and a western diet, promote the induction and expansion of SA T cells, contributing to follicle formation and the pathogenesis of COPD. To further investigate this hypothesis, we characterize the presence of SA T cells consequent to environmental influences in mouse and human lung tissue using immunofluorescence imaging and flow cytometry. In parallel, the molecular mechanisms by which SA T cells promote COPD pathogenesis are investigated via ex vivo induction of SA T cells followed by RNA sequencing analysis. Finally, we will employ a conditional knockout mouse model, subjected to both cigarette smoke exposure and a western diet, to examine the contribution of SA T cells to immune cell infiltration and iBALT formation in the lung. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany