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Prostaglandin I?promotes the development of IL-17-producing ?? T cells that associate with the epithelium during allergic lung inflammation.

ABSTRACT: ?? T cells rapidly produce cytokines and represent a first line of defense against microbes and other environmental insults at mucosal tissues and are thus thought to play a local immunoregulatory role. We show that allergic airway inflammation was associated with an increase in innate IL-17-producing ?? T (??-17) cells that expressed the ?E?7 integrin and were closely associated with the airway epithelium. Importantly, PGI(2) and its receptor IP, which downregulated airway eosinophilic inflammation, promoted the emergence of these intraepithelial ??-17 cells into the airways by enhancing IL-6 production by lung eosinophils and dendritic cells. Accordingly, a pronounced reduction of ??-17 cells was observed in the thymus of naive mice lacking the PGI(2) receptor IP, as well as in the lungs during allergic inflammation, implying a critical role for PGI(2) in the programming of "natural" ??-17 cells. Conversely, iloprost, a stable analog of PGI(2), augmented IL-17 production by ?? T cells but significantly reduced airway inflammation. Together, these findings suggest that PGI(2) plays a key immunoregulatory role by promoting the development of innate intraepithelial ??-17 cells through an IL-6-dependent mechanism. By enhancing ??-17 cell responses, stable analogs of PGI(2) may be exploited in the development of new immunotherapeutic approaches.

SUBMITTER: Jaffar Z

PROVIDER: S-EPMC3208053 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Prostaglandin I₂promotes the development of IL-17-producing γδ T cells that associate with the epithelium during allergic lung inflammation.

Jaffar Zeina Z Ferrini Maria E ME Shaw Pamela K PK FitzGerald Garret A GA Roberts Kevan K

Journal of immunology (Baltimore, Md. : 1950) 20111005 10

γδ T cells rapidly produce cytokines and represent a first line of defense against microbes and other environmental insults at mucosal tissues and are thus thought to play a local immunoregulatory role. We show that allergic airway inflammation was associated with an increase in innate IL-17-producing γδ T (γδ-17) cells that expressed the αEβ7 integrin and were closely associated with the airway epithelium. Importantly, PGI(2) and its receptor IP, which downregulated airway eosinophilic inflamma ...[more]

PMID: 21976777

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Project description:BACKGROUND:IL-17 plays a pathogenic role in asthma. ST2- inflammatory group 2 innate lymphoid cells (ILC2s) driven by IL-25 can produce IL-17, whereas ST2+ natural ILC2s produce little IL-17. OBJECTIVE:We characterized ST2+IL-17+ ILC2s during lung inflammation and determined the pathogenesis and molecular regulation of ST2+IL-17+ ILC2s. METHODS:Lung inflammation was induced by papain or IL-33. IL-17 production by lung ILC2s from wild-type, Rag1-/-, Rorcgfp/gfp, and aryl hydrocarbon receptor (Ahr)-/- mice was examined by using flow cytometry. Bone marrow transfer experiments were performed to evaluate hematopoietic myeloid differentiation primary response gene-88 (MyD88) signaling in regulating IL-17 production by ILC2s. mRNA expression of IL-17 was analyzed in purified naive ILC2s treated with IL-33, leukotrienes, and inhibitors for nuclear factor of activated T cells, p38, c-Jun N-terminal kinase, or nuclear factor ? light-chain enhancer of activated B cells. The pathogenesis of IL-17+ ILC2s was determined by transferring wild-type or Il17-/- ILC2s to Rag2-/-Il2rg-/- mice, which further induced lung inflammation. Finally, expression of 106 ILC2 signature genes was compared between ST2+IL-17+ ILC2s and ST2+IL-17- ILC2s. RESULTS:Papain or IL-33 treatment boosted IL-17 production from ST2+ ILC2s (referred to by us as ILC217s) but not ST2- ILC2s. Ahr, but not retinoic acid receptor-related orphan receptor ?t, facilitated the production of IL-17 by ILC217s. The hematopoietic compartment of MyD88 signaling is essential for ILC217 induction. IL-33 works in synergy with leukotrienes, which signal through nuclear factor of activated T-cell activation to promote IL-17 in ILC217s. Il17-/- ILC2s were less pathogenic in lung inflammation. ILC217s concomitantly expressed IL-5 and IL-13 but expressed little GM-CSF. CONCLUSION:During lung inflammation, IL-33 and leukotrienes synergistically induce ILC217s. ILC217s are a highly pathogenic and unexpected source for IL-17 in lung inflammation.

Project description:BackgroundSerum IL-22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in TH2-dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge-induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL-22.ObjectiveWe sought to determine the role of IL-22 in antigen-driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice.MethodsWild-type (WT) and Il22-/- mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T-cell receptor-specific T cells were TH22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined.ResultsEpicutaneous sensitization preferentially elicited an IL-22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL-22 production, and accumulation of CD3+CD4+IL-22+ T cells that coexpressed IL-17A and TNF-α. Epicutaneously sensitized Il22-/- mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL-13, IL-17A, and TNF-α was normal, but IFN-γ production was increased in lung cells from airway-challenged and epicutaneously sensitized Il22-/- mice. Intranasal instillation of IFN-γ-neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of TH22-polarized WT, but not IL-22-deficient, T-cell receptor OVA-specific T cells, which secrete both IL-17A and TNF-α, had neutrophil-dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL-22 with TNF-α, but not IL-17A, elicited neutrophil-dominated airway inflammation and AHR in WT mice, suggesting that loss of IL-22 synergy with TNF-α contributed to defective recruitment of neutrophils into the airways of Il22-/- mice. TNF-α, but not IL-22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice.ConclusionEpicutaneous sensitization promotes generation of antigen-specific IL-22-producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL-22 plays an important role in the atopic march.

Dataset Information

Prostaglandin I?promotes the development of IL-17-producing ?? T cells that associate with the epithelium during allergic lung inflammation.

Publications

Prostaglandin I₂promotes the development of IL-17-producing γδ T cells that associate with the epithelium during allergic lung inflammation.

Similar Datasets

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