Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses

Moro, Kazuyo; Kabata, Hiroki; Tanabe, M.; Koga, Satoshi; Takeno, Natsuki; Mochizuki, Miho; Fukunaga, Koichi; Asano, Koichiro; Betsuyaku, Tomoko; Koyasu, Shigeo

doi:10.1038/ni.3309

Cited by 351 publications

(437 citation statements)

References 44 publications

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“…Interestingly, we identified ILCs both locally and in the periphery in patients with BCa and observed a skewing toward a group 2 ILC phenotype that was associated with a worsening of the disease. A recent study reported that murine tissue-resident ILC2 expand locally in inflammatory conditions (45). Accordingly, bladder tumors and intravesical BCG stimulation may favor ILC2 proliferation/ induction in the bladder, as supported by in vitro data.…”

Section: Discussionmentioning

confidence: 64%

ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence

Chevalier

Trabanelli

Racle

et al. 2017

Journal of Clinical Investigation

178

151

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Section: Discussionmentioning

confidence: 64%

ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence

Chevalier

Trabanelli

Racle

et al. 2017

Journal of Clinical Investigation

178

151

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“…It has been shown that ILC2s express a number of chemokine receptors, including CCR2, CCR4, CCR5, and CXCR4 under certain conditions. In particular, CXCR4 is only expressed in ILC2s after exposure to IL-33 [37]. RNA transcriptome analysis of intestinal ILC2s has also revealed transcripts for CCR8 and its ligand CCL1 [38].…”

Section: Discussionmentioning

confidence: 99%

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Bruijn

Tindemans

et al. 2016

Eur J Immunol

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Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL-5 and IL-13. Here, we used a house dust mite (HDM)-driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T-cell activation precedes ILC2 induction. During HDM-driven allergic airway inflammation the accumulation of ILC2s in BALF is IL-33 independent, although infiltrating ILC2s produce less cytokines in Il33 −/− mice. Transfer of in vitro polarized OVA-specific OT-II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T-cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM-mediated allergic airway inflammation in mice critically depends on activation of T cells.Keywords: Allergy · Asthma · Group 2 innate lymphoid cells (ILC2s) · House dust mite · Th2 cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAsthma is a heterogeneous disease involving chronic inflammation of the airways and is characterized by episodes of coughing, wheezing, and shortness of breath. Multiple genetic predispositions and environmental factors contribute to asthma development and it is estimated that ß300 million people are affected worldwide. The asthma syndrome is divided into distinct disease entities with specific mechanisms, which have been called asthma endotypes [1,2]. The most prevalent endotype is allergic asthma, showing a strong association between exacerbations and repeated Correspondence: Dr. Rudi W. Hendriks e-mail: r.hendriks@erasmusmc.nl exposure to allergens such as pollen, fungi, or house dust mite (HDM). Allergic asthma is thought to be a classic Th2-mediated disease in which the signature effector cytokines IL-4, IL-5, and IL-13 are key orchestrators of persistent inflammation, airway hyperresponsiveness and remodeling, smooth muscle cell hyperplasia, mucous cell metaplasia, and increased angiogenesis (reviewed in [2,3]).Although production of IL-5 and IL-13 by a non-T/non-B lymphocyte population in response to IL-25 was first reported by Fort et al. [4], only recently these cells were accurately characterized and defined as a novel cell population that is negative for classic hematopoietic lineage markers and expresses Sca-1, CD117 (c-kit), CD25 (IL-2Rα), CD127 (IL-7Rα), and T1/ST2 (IL-33R) [5][6][7]. These innate cells are currently referred to as group 2 innate lymphoid cells (ILC2s) and were found to produce IL-13, which is [24]. Ho...

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“…These findings are in accordance with our observation that IL-27 has an immunoprotective role in Th2-mediated disease allergic asthma. Very recent studies provided evidence that IL-27 as well as type I and type II IFNs are able to suppress group 2 innate lymphoid cell responses in vitro and in vivo (38,40) and suggested that this mechanism is next to IFN-g induction in importance for the immunoregulation via IL-27 of type 2 immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…This heterodimeric cytokine binds to the IL-27 receptor and gp130 to activate STAT1 (33)(34)(35) and induce Th1 cell differentiation (32,36) whereas it directly suppresses Th2 and Th17 differentiation (37). Very recently, it was shown in different models of lung inflammation, including allergic inflammation and viral respiratory tract infection, that IFNs and IL-27 regulate the function of group 2 innate lymphoid cells and thereby together restrict type 2 immune responses (38)(39)(40). Using a model of immune perturbation, Molofsky et al (41) have also shown that a counterregulatory mechanism involving IFN-g and IL-33 is involved in regulating type 2 innate lymphoid cells and thereby maintenance of immune homeostasis.…”

mentioning

confidence: 99%

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

Jirmo

Daluege

Happle

et al. 2016

The Journal of Immunology

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Different models of experimental allergic asthma have shown that the TLR7/8 agonist resiquimod (R848) is a potential inhibitor of type 2 helper cell–driven inflammatory responses. However, the mechanisms mediating its therapeutic effects are not fully understood. Using a model of experimental allergic asthma, we show that induction of IL-27 by R848 is critical for the observed ameliorative effects. R848 significantly inhibited all hallmarks of experimental allergic asthma, including airway hyperreactivity, eosinophilic airway inflammation, mucus hypersecretion, and Ag-specific Ig production. Whereas R848 significantly reduced IL-5, IL-13, and IL-17, it induced IFN-γ and IL-27. Neutralization of IL-27 completely reversed the therapeutic effect of R848 in the experimental asthma model, demonstrating dependence of R848-mediated suppression on IL-27. In vitro, R848 induced production of IL-27 by murine alveolar macrophages and dendritic cells and enhanced expression of programmed death–ligand 1, whose expression on monocytes and dendritic cells has been shown to regulate peripheral tolerance in both murine and human studies. Moreover, in vitro IL-27 enhanced secretion of IFN-γ whereas it inhibited IL-5 and IL-13, demonstrating its direct effect on attenuating Th2 responses. Taken together, our study proves that R848-mediated suppression of experimental asthma is dependent on IL-27. These data provide evidence of a central role of IL-27 for the control of Th2-mediated allergic diseases.

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Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses

Cited by 351 publications

References 44 publications

ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence

ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

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