T cell- and eosinophil-driven gut-lung interaction in the resolution of asthma

• Applicants: Professorin Susetta Finotto, Ph.D.; Professor Dr. Sebastian Zundler
• Subject Area: Pneumology, Thoracic Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534888930

Asthma and colitis share common disturbance of the epithelial barrier function and a local T cell mediated pathologic immune response to otherwise innocuous antigens. However, the mechanisms of this link and how intestinal immunity might shape pulmonary immune responses remains unknown. In this project, we want to investigate gut-to-lung crosstalk in the context of chronic inflammation to explore how gut-lung interaction can be targeted to resolve inflammation in the lung. Recently, we discovered an unpredicted role of IL-3 in the resolution of asthma by driving the expansion of regulatory T cells. These data indicate that administration of IL-3 might be a promising future strategy for the treatment of both asthma and colitis and that it might also impact on inter-organ cell trafficking. Further, preliminary data indicate that, following experimental colitis, the frequency of pro-inflammatory eosinophils expressing the IL5 receptor alpha in the lung of mice is increased. Analysis of single cell RNA-sequencing data of human lung T cells from asthma patients showed that a substantial portion expresses integrin α4β7 indicating that these T cells have been primed in the gut. Thus, we hypothesize that intestinal inflammation triggers T cell and eosinophil trafficking to the lung that subsequently predisposes for independent chronic inflammatory pathology there, whereas IL-3 might counteract this process and promote immunologic homeostasis to resolve asthma. To investigate this hypothesis, we will study the interdependence of experimental colitis and asthma in IL-3/IL-3Ralpha-deficient and-proficient mice using sequential colitis and asthma models in vivo. We will also study cell trafficking pathways and cell mechanical properties along the gut-lung axis, address the interplay with the intestinal microbiome and characterize gut-derived immune cells in the lung by single cell transcriptomics. In a translational aim, we will study gut-lung interaction in patients with asthma and/or IBD and target T cells in the gut to modulate trafficking to and pathology in the lung in experimental models. Finally, we will explore dietary interventions to regulate asthma via changes in the intestine. These studies should lead to a better understanding of immune cell trafficking from the gut to the lungs and thus to set up new interventional strategies for resolving asthma.

• DFG Programme: Research Grants