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

Abstract

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...

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

“…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).…”

Outstanding animal studies in allergy I. From asthma to food allergy and anaphylaxis

“…1, from [39]) [29,34,40] or by surgically implanted means [23,24,27]. Studies investigating the mechanisms at the very start of allergic sensitization demonstrated that B-cells are dispensable for the primary CD4 + T-cell response, but crucial for expansion of primed Th2 cells and generation of central memory [28 ▪▪ ], ILC 2 were not an early source of Th2 cytokines, but contributed to allergic inflammation [26] together with IL-33 derived from monocytes [24], IL-23 secreted by bronchial epithelial cells [32], placenta growth factor [27] and lysophophatidylcholine [36]. Th2 and Th17 inflammatory pathways seemed to be reciprocally regulated in asthma [41].…”

Birch pollen‐specific subcutaneous immunotherapy reduces ILC2 frequency but does not suppress IL‐33 in mice

“…BP SCIT treatment greatly reduced the number of BALF and lung ILC2s (Figure A, identified as Lin − [CD3 − CD19 − B220 − DX5 − FcɛRI − GR‐1 − CD11c − ],CD45 + , ST2 + , CD127 + , CD25 + in BALF and in lung). Li et al demonstrated that accumulation of ILC2s is dependent on the presence of Th2 cells. BP SCIT decreased the Th2 cytokine production in the lung draining lymph nodes (Figure A) and largely inhibited the accumulation of T cells to the bronchoalveolar compartment (Figure B).…”

“…BAL inflammatory cells were obtained by intratracheal cannulation, and the airway lumen was lavaged 3× with the same millilitre PBS containing 0.1 mmol/L EDTA. Cell differentiation was done by flow cytometric analysis as described before . BALF was stored at −20°C until IL‐5 was determined by ELISA (Ready set go!, eBioscience Inc via Immunosource, Halle‐Zoersel, Belgium).…”

“…This innate lymphoid cell type functions beyond the induction of the primary inflammatory response to the allergen and fulfils a prominent role in the maintenance of chronic asthma. The relative contribution of Th2 cells vs ILC2s is still under debate . The epithelium secretes innate inflammatory cytokines, like IL‐33, IL‐25, TSLP and GM‐CSF, after an encounter with allergens but possibly also after nonallergenic stimuli (eg cold air) .…”