Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures

Gold, Matthew; Antignano, Frann; Halim, Timotheus Y.F.; Hirota, Jeremy A.; Blanchet, Marie‐Renée; Zaph, Colby; Takei, Fumio; McNagny, Kelly M.

doi:10.1016/j.jaci.2014.02.033

Cited by 182 publications

(180 citation statements)

References 30 publications

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“…ILC2s were shown to have the capacity to enhance differentiation of naive CD4 + T cells to a Th2 phenotype while inhibiting Th1 differentiation in a contactdependent manner [16,17]. Together with analyses in helminth infection models showing that Th2 responses are impaired in the absence of ILC2s [18,19], these findings support a model in which ILC2s are "early sentinel" cells that can be rapidly activated to connect innate and adaptive immunity by acting as an early innate source of type 2 cytokines. In strong contrast, Rag1 −/− mice that lack T and B cells fail to develop significant airway inflammation and hyperresponsiveness upon exposure to Aspergillus [20].…”

Section: Introductionsupporting

confidence: 52%

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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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Section: Introductionsupporting

confidence: 52%

“…responses [12][13][14][15]18]. However, the contribution of ILC2s in HDM-induced allergic inflammation and the mechanisms that link ILC2 activation and the adaptive immune system are not completely understood.…”

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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“…critical to the development of a type-2 immune response (15)(16)(17)(18)(19)(20). Thus far, there has been little evidence implicating sPLA 2 -X as a regulator of these responses; however, a recent paper examining the effect of bee venom PLA 2 (bvPLA 2 ) in the periphery demonstrated that bvPLA 2 induces the release of IL-33, leading to the generation of ILC2s and subsequent antigen-specific T cell responses (21).…”

Section: Introductionmentioning

confidence: 99%

Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen

et al. 2017

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“…Furthermore, Rora sg/sg BMT animals are protected from type 2 immune lung pathology (22)(23)(24). In this report, we used a similar strategy to evaluate their role in a Salmonella-induced model of gut fibrosis.…”

Section: Introductionmentioning

confidence: 99%

The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease

Gold

Hughes

et al. 2016

Sci. Immunol.

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Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. In Crohn's disease, this manifests itself as recurrent gastrointestinal strictures for which there is no effective therapy beyond surgical intervention. Using a model of infection-induced chronic gut inflammation, we show that Rora-deficient mice are protected from fibrosis; infected intestinal tissues display diminished pathology, attenuated collagen deposition and reduced fibroblast accumulation. Although Rora is best known for its role in ILC2 development, we find that Salmonella-induced fibrosis is independent of eosinophils, STAT6 signaling and Th2 cytokine production arguing that this process is largely ILC2-independent. Instead, we observe reduced levels of ILC3-and T cellderived IL-17A and IL-22 in infected gut tissues. Furthermore, using Rora sg/sg /Rag1 −/− bone marrow chimeric mice, we show that restoring ILC function is sufficient to re-establish IL-17A and IL-22 production and a profibrotic phenotype. Our results show that RORα-dependent ILC3 functions are pivotal in mediating gut fibrosis and they offer an avenue for therapeutic intervention in Crohn's-like diseases.

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Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures

Cited by 182 publications

References 30 publications

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

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

Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen

The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease

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