IL-33 Promotes the Induction and Maintenance of Th2 Immune Responses by Enhancing the Function of OX40 Ligand

Murakami-Satsutani, Naoko; Ito, Tomoki; Nakanishi, Teruyuki; Inagaki, Noriko; Tanaka, Akihiro; Vien, Phan Thi Xuan; Kibata, Kayoko; Inaba, Muneo; Nomura, Shosaku

doi:10.2332/allergolint.13-oa-0672

Cited by 105 publications

(64 citation statements)

References 63 publications

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“…59,60 By contrast, recent work in human subjects showed that IL-33, which mediates its effects through its receptor, ST2, did not induce OX40L on human CD11c + DCs. 56 Nonetheless, IL-33 increased T H 2 polarization by TSLP-primed human DCs or by OX40L alone, suggesting an ability to augment the TSLP/OX40L axis. In the same study IL-33 also acted directly on naive T cells to promote T H 2-like cells expressing IL-5, IL-9, and IL-13.…”

Section: Tslpmentioning

confidence: 90%

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Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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Asthma encompasses a variety of clinical phenotypes that involve distinct T cell–driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell “hubs” are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell–based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

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Section: Tslpmentioning

confidence: 90%

“…56–58 In mice, both IL-25 and IL-33 induce OX40L on DCs. 59,60 By contrast, recent work in human subjects showed that IL-33, which mediates its effects through its receptor, ST2, did not induce OX40L on human CD11c + DCs.…”

Section: Tslpmentioning

confidence: 99%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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“…IL-33 also acts in synergy for promoting Th2 differentiation by DCs. It has been reported that IL-33 works as a positive regulator of TSLP-DC-OX40L axis by the increased production of IL-5, IL-9, and IL-13, which initiates and maintains the Th2 cell-mediated inflammatory responses [87]. Moreover, IRF4 also modulates IL-33 cytokine production in DCs to specifically promote Th2 differentiation and inflammation [78].…”

Section: Il-33/st2l In Dcsmentioning

confidence: 98%

The role of IL-33/ST2L signals in the immune cells

et al. 2015

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“…IL-33 will amplify antigen-dependent and antigenindependent effector responses from both human and mouse T H 2 cells (16,17). One recent study revealed that IL-33 can enhance TSLP-and DC-mediated human T H 2 memory responses in vitro, suggesting the alarmins could play a role in maintaining immune responses (23). Although TSLP, IL-25, and IL-33 have all been shown to promote type 2 immunity when overexpressed in mice (10)(11)(12), the requirement for these cytokines in the development of type 2 immunity in response to allergens and helminth parasites has been more variable, with some studies identifying little to no role for TSLP, IL-25, or IL-33 when targeted individually (24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine–driven inflammation and fibrosis

et al. 2016

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*Thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33 are important initiators of type 2-associated mucosal inflammation and immunity. However, their role in the maintenance of progressive type 2 inflammation and fibrosis is much less clear. Using chronic models of helminth infection and allergic lung inflammation, we show that collective disruption of TSLP, IL-25, and IL-33 signaling suppresses chronic and progressive type 2 cytokinedriven inflammation and fibrosis. In a schistosome lung granuloma model or during chronic Schistosoma mansoni infection in the liver, individual ablation of TSLP, IL-25, or IL-33/ST2 had no impact on the development of IL-4/ IL-13-dependent inflammation or fibrosis. However, significant reductions in granuloma-associated eosinophils, hepatic fibrosis, and IL-13-producing type 2 innate lymphoid cells (ILC2s) were observed when signaling of all three mediators was simultaneously disrupted. Combined blockade through monoclonal antibody (mAb) treatment also reduced IL-5 and IL-13 expression during primary and secondary granuloma formation in the lungs. In a model of chronic house dust mite-induced allergic lung inflammation, combined mAb treatment did not decrease established inflammation or fibrosis. TSLP/IL-33 double-knockout mice treated with anti-IL-25 mAb during priming, however, displayed decreased inflammation, mucus production, and lung remodeling in the chronic phase. Together, these studies reveal partially redundant roles for TSLP, IL-25, and IL-33 in the maintenance of type 2 pathology and suggest that in some settings, early combined targeting of these mediators is necessary to ameliorate progressive type 2-driven disease.

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IL-33 Promotes the Induction and Maintenance of Th2 Immune Responses by Enhancing the Function of OX40 Ligand

Abstract: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.

Cited by 105 publications

References 63 publications

Pathogenic CD4 + T cells in patients with asthma

Pathogenic CD4 + T cells in patients with asthma

The role of IL-33/ST2L signals in the immune cells

Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine–driven inflammation and fibrosis

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