P07 - Deciphering the involvement of adaptive tissue immune cells in airway loss pathogenesis in COPD

The loss of the smallest conducting airways, specifically the terminal and preterminal bronchioles, represents an early pathological change in the lungs of individuals with COPD. This can be observed even before the occurrence of emphysematous tissue destruction. Remarkably, over 41% of terminal bronchioles are lost by the time a patient is diagnosed with mild COPD. Notably, lymphoid and myeloid cells, including tissue T cells and macrophages, accumulate in the distal airways, suggesting a potential role in driving the loss of small airways. This project aims to elucidate the relative cellular contributions and disease-specific pathogenic mechanisms in response to cigarette smoke. We will specifically focus on the role of immune cells, particularly activated tissue T cells, in triggering molecular pathways in the epithelial cells of terminal and preterminal bronchioles, leading to their loss. We have single-cell RNA sequencing (scRNA-seq) data on hand from various COPD disease stages, including the so-called Pre-COPD stage. Our goal is to identify the primary epithelial subpopulation affected across disease stages and correlate it with the presence of tissue T cells. We will also investigate the type of interaction between immune and epithelial cells. Using our established in vivo systems, as well as ex vivo organoids and precision-cut lung slices (PCLS) readouts, we will explore the role of lung tissue T cells in the context of small airway loss.

Project-related publications:

1. Conlon TM, Yildirim AÖ. Oxysterol metabolism dictates macrophage influx during SARS-CoV-2 infection. Eur Respir J. 2023 Mar 9;61(3):2202417. doi: 10.1183/13993003.02417-2022.
2. Spix B, Butz ES, Chen CC, Rosato AS, Tang R, Jeridi A, Kudrina V, …, Gudermann T, Wahl-Schott C, Bracher F, Yildirim AÖ, Biel M, Grimm C. Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. Nat Commun. 2022 Jan 14;13(1):318. doi: 10.1038/s41467-021-27860-x. PMID: 35031603; PMCID: PMC8760276.
3. Conlon TM, John-Schuster G, Heide D, Pfister D, Lehmann M, Hu Y, Ertüz Z, Lopez MA, Ansari M, Strunz M, Mayr C, Angelidis I, Ciminieri C, Costa R, Kohlhepp MS, Guillot A, Günes G, Jeridi A, Funk MC, …, Heikenwalder M, Yildirim AÖ. Inhibition of LTβR signalling activates WNT-induced regeneration in lung. Nature. 2020 Dec;588(7836):151-156. doi: 10.1038/s41586-020-2882-8. Epub 2020 Nov 4.
4. Günes Günsel G*, Conlon TM*, Jeridi A*, Kim R, Ertüz Z, Lang NJ, Ansari M, Novikova M, Jiang D, Strunz M, Gaianova M, Hollauer C, Gabriel C, Angelidis I, Doll S, …, Heissmeyer V, Rinkevich Y, Bayram H, Schiller HB, Conrad M, Schneider R, Yildirim AÖ. The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD. Nat Commun. 2022 Mar 14;13(1):1303. doi: 10.1038/s41467-022-28809-4. PMID: 35288557; PMCID: PMC8921220.
5. Wu X, Bos IST, Conlon TM, Ansari M, Verschut V, van der Koog L, Verkleij LA, D'Ambrosi A, Matveyenko A, Schiller HB, Königshoff M, Schmidt M, Kistemaker LEM, Yildirim AÖ, Gosens R. A transcriptomics-guided drug target discovery strategy identifies receptor ligands for lung regeneration Sci Adv. 2022 Mar 25;8(12):eabj9949.