Khan Matarr, Alteneder Marlis, Reiter Wolfgang, Krausgruber Thomas, Dobnikar Lina, Madern Moritz, Waldherr Monika, Bock Christoph, Hartl Markus, Ellmeier Wilfried, Henriksson Johan, Boucheron Nicole
Medical University of Vienna, Center of Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division of Immunobiology, Vienna, Austria.
Max Perutz Labs, Mass Spectrometry Facility, Vienna Biocenter Campus (VBC), Vienna, Austria.
Nat Commun. 2025 Mar 15;16(1):2565. doi: 10.1038/s41467-025-57590-3.
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.
肺致病性2型辅助性T细胞（pTh2）在介导过敏性哮喘中起重要作用，但关于其异质性和表观遗传调控仍存在一些基本问题。在这里，我们通过对暴露于屋尘螨的小鼠进行单细胞RNA测序，在有和没有组蛋白去乙酰化酶1（HDAC1）功能的情况下，研究过敏性哮喘中的免疫调节。我们的分析表明肺pTh2细胞有两个不同的高度促炎亚群，并确定胸腺基质淋巴细胞生成素（TSLP）和肿瘤坏死因子受体超家族（TNFRSF）成员是体外产生pTh2细胞的重要驱动因素。利用我们的体外模型，我们揭示了TSLP和一个TNFRSF成员通过调节HDAC1的抑制功能，如何在2型细胞因子基因位点塑造染色质可及性。总之，我们对pTh2细胞生物学有了深入了解，并建立了一个用于研究pTh2细胞的体外模型，该模型被证明有助于发现参与pTh2介导的过敏性哮喘的分子机制。
