Single-cell and Chromatin Accessibility Profiling Reveals Regulatory Programs of Pathogenic Th2 Cells in Allergic Asthma

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Mar 16

PMID 40089475

Authors

Matarr Khan

Marlis Alteneder

Wolfgang Reiter

Thomas Krausgruber

Lina Dobnikar

Moritz Madern

Monika Waldherr

Christoph Bock

Markus Hartl

Wilfried Ellmeier

Johan Henriksson

Nicole Boucheron

Affiliations

Soon will be listed here.

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.

References

Lambrecht B, Hammad H . The immunology of asthma. Nat Immunol. 2014; 16(1):45-56. DOI: 10.1038/ni.3049. View

Porsbjerg C, Melen E, Lehtimaki L, Shaw D . Asthma. Lancet. 2023; 401(10379):858-873. DOI: 10.1016/S0140-6736(22)02125-0. View

Leon B, Ballesteros-Tato A . Modulating Th2 Cell Immunity for the Treatment of Asthma. Front Immunol. 2021; 12:637948. PMC: 7902894. DOI: 10.3389/fimmu.2021.637948. View

Willart M, Lambrecht B . The danger within: endogenous danger signals, atopy and asthma. Clin Exp Allergy. 2008; 39(1):12-9. DOI: 10.1111/j.1365-2222.2008.03118.x. View

Islam S, Luster A . T cell homing to epithelial barriers in allergic disease. Nat Med. 2012; 18(5):705-15. PMC: 3863331. DOI: 10.1038/nm.2760. View

Walker J, McKenzie A . T2 cell development and function. Nat Rev Immunol. 2017; 18(2):121-133. DOI: 10.1038/nri.2017.118. View

Mitson-Salazar A, Yin Y, Wansley D, Young M, Bolan H, Arceo S . Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function. J Allergy Clin Immunol. 2015; 137(3):907-18.e9. DOI: 10.1016/j.jaci.2015.08.007. View

Lam E, Kariyawasam H, Rana B, Durham S, McKenzie A, Powell N . IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa. J Allergy Clin Immunol. 2015; 137(5):1514-24. PMC: 4852988. DOI: 10.1016/j.jaci.2015.10.019. View

Seumois G, Zapardiel-Gonzalo J, White B, Singh D, Schulten V, Dillon M . Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma. J Immunol. 2016; 197(2):655-64. PMC: 4936908. DOI: 10.4049/jimmunol.1600397. View

10.

Vieira Braga F, Kar G, Berg M, Carpaij O, Polanski K, Simon L . A cellular census of human lungs identifies novel cell states in health and in asthma. Nat Med. 2019; 25(7):1153-1163. DOI: 10.1038/s41591-019-0468-5. View

11.

Islam S, Chang D, Colvin R, Byrne M, McCully M, Moser B . Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ T(H)2 cells. Nat Immunol. 2011; 12(2):167-77. PMC: 3863381. DOI: 10.1038/ni.1984. View

12.

Endo Y, Hirahara K, Iinuma T, Shinoda K, Tumes D, Asou H . The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity. 2015; 42(2):294-308. DOI: 10.1016/j.immuni.2015.01.016. View

13.

Nobs S, Natali S, Pohlmeier L, Okreglicka K, Schneider C, Kurrer M . PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation. J Exp Med. 2017; 214(10):3015-3035. PMC: 5626395. DOI: 10.1084/jem.20162069. View

14.

Tibbitt C, Stark J, Martens L, Ma J, Mold J, Deswarte K . Single-Cell RNA Sequencing of the T Helper Cell Response to House Dust Mites Defines a Distinct Gene Expression Signature in Airway Th2 Cells. Immunity. 2019; 51(1):169-184.e5. DOI: 10.1016/j.immuni.2019.05.014. View

15.

Ihara F, Sakurai D, Yonekura S, Iinuma T, Yagi R, Sakurai T . Identification of specifically reduced Th2 cell subsets in allergic rhinitis patients after sublingual immunotherapy. Allergy. 2018; 73(9):1823-1832. DOI: 10.1111/all.13436. View

16.

Nakayama T, Hirahara K, Onodera A, Endo Y, Hosokawa H, Shinoda K . Th2 Cells in Health and Disease. Annu Rev Immunol. 2016; 35:53-84. DOI: 10.1146/annurev-immunol-051116-052350. View

17.

Bertschi N, Bazzini C, Schlapbach C . The Concept of Pathogenic TH2 Cells: Collegium Internationale Allergologicum Update 2021. Int Arch Allergy Immunol. 2021; 182(5):365-380. DOI: 10.1159/000515144. View

18.

Tripathi S, Lahesmaa R . Transcriptional and epigenetic regulation of T-helper lineage specification. Immunol Rev. 2014; 261(1):62-83. PMC: 4255756. DOI: 10.1111/imr.12204. View

19.

Tumes D, Papadopoulos M, Endo Y, Onodera A, Hirahara K, Nakayama T . Epigenetic regulation of T-helper cell differentiation, memory, and plasticity in allergic asthma. Immunol Rev. 2017; 278(1):8-19. DOI: 10.1111/imr.12560. View

20.

Shakespear M, Halili M, Irvine K, Fairlie D, Sweet M . Histone deacetylases as regulators of inflammation and immunity. Trends Immunol. 2011; 32(7):335-43. DOI: 10.1016/j.it.2011.04.001. View