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Bulk RNA-seq of ILC2, Tconv, Th2, Treg Gata3hi and Treg Gatalo from the lungs of IL-33 treated mice

ABSTRACT: Regulatory T cells (Tregs) are essential for limiting adaptive immunity, and restrain type-2 inflammation in allergic disease. As Tregs function locally, the mechanisms that coordinate their suppressive role in the inflamed niche are of great interest. Here we show that group 2 innate lymphoid cells (ILC2) are critical mediators of IL-33-driven Treg expansion in allergic inflammation. ILC2-derived OX40L promotes the local expansion of Gata3high Tregs, which possess distinct transcriptional and functional programmes that enforce co-localisation with ILC2 in the inflamed airways. Using OX40 Treg-conditional mutant mice, we show that Gata3high Tregs are important for restraining adaptive type-2 immunity. Mechanistically, Gata3high Tregs modulate OX40L bioavailability on ILC2, which controls effector memory Th2 cell formation. As such, ILC2 can simultaneously engage both the effector and regulatory arms of adaptive type-2 immunity via the OX40L-OX40 signalling axis. More specifically, ILC2-Treg interactions serve as a critical feedback mechanism to control adaptive type-2 immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE230597 | GEO | 2024/07/19

REPOSITORIES: GEO

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Project description:Allergic airway inflammation is a chronic inflammatory condition resulting from uncontrolled immune responses to environmental antigens. While it is well-established that allergic immune responses exhibit a high degree of diversity, driven by primary effector cell types like eosinophils, neutrophils, or CD4 T cells with distinct effector signatures, the exact mechanisms responsible for such pathogenesis remain largely elusive. Foxp3+ regulatory T cells (Treg) is an indispensable immune regulator during chronic inflammation including allergic airway inflammation. Emerging evidence suggests that Tregs infiltrating inflamed tissues exhibit distinct phenotypes dependent on the specific tissue sites and can display significant heterogeneity and tissue residency. Whether diverse allergic inflammatory responses in the lung influences infiltrating Treg heterogeneity or Treg lung residency has not previously been explored. We employed an unbiased single-cell RNAseq approach to study lung-infiltrating Tregs in models of eosinophilic and neutrophilic airway inflammation models, in which Tregs are critical immune regulators of inflammation. We found that lung-infiltrating Tregs are highly heterogeneous and that Tregs displaying lung residency phenotypes are significantly different depending on the types of inflammation. Tregs expression of ST2, a receptor for alarmin cytokine IL-33, was predominantly induced by eosinophilic inflammation and by tissue residency. However, Treg-specific ST2 deficiency did not affect the development of eosinophilic allergic inflammation nor the generation of lung resident Tregs. These results uncover a striking heterogeneity among Tregs infiltrating the lungs during allergic airway inflammation. The results also indicate that varying types of inflammation may give rise to phenotypically distinct lung resident Tregs. Thus, the present study underscores a novel mechanism by which inflammatory environments may shape the composition of infiltrating Tregs, allowing them to regulate inflammatory responses through tissue-adapted mechanisms.

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Bulk RNA-seq of ILC2, Tconv, Th2, Treg Gata3hi and Treg Gatalo from the lungs of IL-33 treated mice

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