Single-cell and chromatin accessibility profiling reveals regulatory programs of pathogenic Th2 cells in allergic asthma

Matarr Khan, Marlis Alteneder, Wolfgang Reiter, Thomas Krausgruber, Lina Dobnikar, Moritz Madern, Monika Waldherr, Christoph Bock, Markus Hartl, Wilfried Ellmeier, Johan Henriksson and Nicole Boucheron ()
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Matarr Khan: Medical University of Vienna, Center of Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division of Immunobiology
Marlis Alteneder: Medical University of Vienna, Center of Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division of Immunobiology
Wolfgang Reiter: Max Perutz Labs, Mass Spectrometry Facility, Vienna Biocenter Campus (VBC)
Thomas Krausgruber: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Lina Dobnikar: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Moritz Madern: Medical University of Vienna, Center of Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division of Immunobiology
Monika Waldherr: Medical University of Vienna, Center of Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division of Immunobiology
Christoph Bock: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Markus Hartl: Max Perutz Labs, Mass Spectrometry Facility, Vienna Biocenter Campus (VBC)
Wilfried Ellmeier: Medical University of Vienna, Center of Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division of Immunobiology
Johan Henriksson: Umeå University, Umeå Centre for Microbial Research (UCMR), Integrated Science Lab (Icelab), Department of Molecular Biology
Nicole Boucheron: Medical University of Vienna, Center of Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division of Immunobiology

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Lung pathogenic T helper type 2 (pTh2) cells are important in mediating allergic asthma, but fundamental questions remain regarding their heterogeneity and epigenetic regulation. Here we investigate immune regulation in allergic asthma by single-cell RNA sequencing in mice challenged with house dust mite, in the presence and absence of histone deacetylase 1 (HDAC1) function. Our analyses indicate two distinct highly proinflammatory subsets of lung pTh2 cells and pinpoint thymic stromal lymphopoietin (TSLP) and Tumour Necrosis Factor Receptor Superfamily (TNFRSF) members as important drivers to generate pTh2 cells in vitro. Using our in vitro model, we uncover how signalling via TSLP and a TNFRSF member shapes chromatin accessibility at the type 2 cytokine gene loci by modulating HDAC1 repressive function. In summary, we have generated insights into pTh2 cell biology and establish an in vitro model for investigating pTh2 cells that proves useful for discovering molecular mechanisms involved in pTh2-mediated allergic asthma.

Date: 2025
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DOI: 10.1038/s41467-025-57590-3

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