The messenger between worlds: the regulation of innate and adaptive type-2 immunity by innate lymphoid cells.

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Article Type: Invited Review

The messenger between worlds: the regulation of innate and adaptive type-2 immunity by innate lymphoid cells

S.T. Scanlon and A.N.J. McKenzie

MRC Laboratory of Molecular Biology Protein & Nucleic Acid Chemistry (PNAC) Division Francis Crick Avenue, Cambridge CB2 0QH UK Tel. No. +44 1223 267164 Fax No. +44 1223 213556 [email protected]

S.T. Scanlon and A.N.J. McKenzie

Abstract Although type-2 immune responses evolved primarily to defend against extracellular helminths, in part through the co-opting of tissue repair and remodelling mechanisms, it is often inappropriately directed towards relatively innocuous allergens resulting in

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cea.12464 This article is protected by copyright. All rights reserved.

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conditions including asthma, allergic rhinitis, food allergy, and atopic dermatitis.

The

recent discovery of group 2 innate lymphoid cells (ILC2) has increased our understanding of the initiation of these responses and the roles played by CD4+ T helper (TH) 2 cells in their modulation. This review focuses on the important messenger role of ILC2 in translating epithelial-derived alarmins into downstream adaptive type-2 responses via dendritic cells and T cells, with special emphasis on their roles in allergic disease.

Introduction The extensive and co-ordinated crosstalk between innate and adaptive immunity is essential for effective defence against the multifarious pathogens encountered by the host throughout its lifetime. T helper 1 (TH1, type-1) and T helper TH17 cell-associated immune responses, characterised by pro-inflammatory cytokines including interferon (IFN)-γ, and IL-17, respectively, combat rapidly dividing microorganisms, such as bacteria, viruses, fungi, and protozoa at the risk of collateral tissue damage.

By contrast, the

type-2 response appears to have evolved to isolate, destroy and expel extracellular helminths, in part through the co-opting of tissue repair and remodelling mechanisms. Type-2 immune responses are usually characterised by the expression of classical effector type-2 cytokines, most notably IL-4, IL-5, IL-9, and IL-13, which direct B-cell class

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switching to IgG1 and IgE, the recruitment and activation of effector cells including mast cells (MCs), basophils, and eosinophils, goblet-cell hyperplasia, mucus production, and smooth muscle contraction.

However, the inappropriate initiation of type-2 immune

responses is associated with several inimical conditions including asthma, allergic rhinitis, food allergy, and atopic dermatitis.

CD4+ TH2 cells had been thought to play the central role in type-2 immune responses due to their capacity to recognise a prodigious number of foreign molecular antigens and to secrete the repertoire of classical type-2 effector cytokines. However, the observation that recombinase activating gene (RAG)-2 knockout animals, which lack B and T cells, were still able to mount type-2 responses cast some doubt on this principle [1-3].

The discovery and characterisation of group-2 innate lymphoid cells

(ILC2), variously termed nuocytes [4, 5], natural helper cells (NHCs) [6], and innate helper 2 cells (Ih2s) [7], have now revealed a previously unappreciated transition from innate to adaptive type-2 immunity.


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In this review, we will focus on the cytokines that induce type-2 immunity, the induction of ILC2 in allergic disease, and the interaction of ILC2 with dendritic cells (DCs) and T cells in the transition to TH2-cell-mediated adaptive immunity.

Type-2 initiator cytokines and the primary role of the epithelium Through their expression of a host of immune regulatory molecules including chemokines and prostaglandins, and those involved in antigen-presentation and costimulation, epithelial cells have been of particular interest recently due to their production of a triad of important type-2 initiating cytokines [8].

Prior to the identification of ILC2, the cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) had all been shown to induce type-2 immunity, and are now known to act as potent activators of ILC2.

Indeed, this common activation of ILC2

explains, in part, the functional overlap of these cytokines. Administration of either IL-25 or IL-33 induces eosinophilia, IgE secretion, type-2 cytokine production, goblet-cell hyperplasia, and mucus production [1, 9]. However, this apparent functional redundancy is likely to represent a simplistic interpretation of a regulatory system that may be


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triggered by different antigens at distinct anatomical sites dependent on individual cytokine ligand and receptor expression.

IL-25 (IL-17E) is a member of the IL-17 family of structurally similar, but functionally diverse cytokines, that is associated with type-2 inflammation and pathology [1, 2, 10].

IL-25 binds to IL-17RB (IL-17BR, IL-25R, IL-17Rh1), which forms a receptor

complex with IL-17RA. Indeed, studies utilizing Il17rb− /− and Il17ra− /− mice have confirmed that both subunits are essential for IL-25 responses in the intestine and lung [11]. Il25 transcription has been detected in TH2 cells, MCs, alveolar macrophages (Mφ), basophils, eosinophils, and lung and intestinal epithelium [12-17], and this cytokine has been reported to stimulate smooth muscle cells, eosinophils, TH2 cells, CD1d-restricted NKT cells (Vα14i-NKT) cells, MPPtype2 cells, and ILCs [5, 15, 18-24]. Mice deficient for IL25 exhibit delayed type-2 responses that fail to expel parasitic helminth infections efficiently [4, 14].

Interleukin-33 (IL-33) is the functional ligand for the IL-1 receptor family member ST2 (encoded by Il1lr1) [9] in complex with IL-1R accessory protein (IL1RAP) [25]. Unlike other type-2-inducing cytokines, IL-33 is not normally secreted, and is found localised to


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heterochromatin in the nucleus, leading to suggestions that it may act as a transcriptional repressor [26]. IL-33 is expressed in various tissues including the central nervous system (CNS), skin, colon, lung and lymphatics and in cell populations including DCs, Mφ and lung epithelial cells [9]. Trichuris infection increased IL-33 expression in the colon, peaking three days post-infection [27]. IL1RAP is broadly expressed [28], whereas the membrane bound form of ST2 is restricted primarily to MCs, basophils, eosinophils, ILC2, and TH2 cells [5, 9, 29-33]. It remains unclear whether IL-33 is secreted, and it may only be released upon cell damage/injury as an alarmin. Il1lr1− /− mice have a defect in the induction of the type-2 cytokine responses after the intravenous administration of

Schistosoma mansoni eggs [34], and Il1rap− /− mice fail to respond to IL-33 administration [25].

Although initially discovered in the context of thymic stroma [35, 36], TSLP is primarily secreted by keratinocytes, as well as small airway and intestinal epithelium [3638] and binds with high affinity to a heterodimeric receptor consisting of the IL-7Rα chain and a unique TSLPR chain reminiscent of the common cytokine receptor γ chain (γc) [37, 39]. A role for TSLP in the initiation of type-2 responses is supported by the finding that TSLP receptor-deficient mice have a defect in type-2 immunity, but normal


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type-1 responses [40-42]. In addition to eliciting ILC2, TSLP has been shown to stimulate the differentiation and activation of CD11c+ DCs, inducing OX40L expression [43, 44], provoking the production of the TH2-cell chemoattractants CCL17 and CCL22 [37, 38], inhibiting IL-12 secretion in the context of type-2 innate ligands [42, 45, 46], and affecting B-cell development and survival [35, 36, 39, 47-51]. Additionally, TSLP has been shown to induce the production of IL-4 by TH2 cells and several type-2 cytokines by MCs but in conjunction with mediators such as IL-1, TNF-α, or IL-33 [29, 52].

ILC2 transcriptional and cell-surface phenotype ILC are lymphoid cells that develop independently of the recombination activating genes (rag1 and rag2) and thus lack rearranged antigen receptors, and do not express markers associated with other immune cell lineages (Lin). ILC can be divided into three subsets — group 1 ILC (ILC1 and NK cells), group 2 ILC (ILC2), and group 3 ILC (ILC3 and LTi cells), depending on their capacity to secrete type-1, type-2, and TH17 cell-associated cytokines, respectively [53, 54]. Murine ILC2 lack surface markers associated with other major haematopoetic lineages (Lin− ), but have been shown to express CD25 (IL-2Rα), CD69, CD90 (Thy1), CD117 (c-Kit), CD127 (IL-7Rα), and Sca-1, as well as CD278 (ICOS), T1/ST2 (IL-33R), and IL-17RB (IL-25R). In man, ILC2 are commonly identified as Lin− cells that


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108 Kamekura R, Kojima T, Takano K, Go M, Sawada N, Himi T. The role of IL-33 and its receptor ST2 in human nasal epithelium with allergic rhinitis. Clin Exp Allergy. 2012;42(2):218-28. 109 Ballantyne SJ, Barlow JL, Jolin HE, Nath P, Williams AS, Chung KF, et al. Blocking IL25 prevents airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol. 2007;120(6):1324-31. 110 Lohning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC, et al. T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc Natl Acad

Sci U S A. 1998;95(12):6930-5. 111 Coyle AJ, Lloyd C, Tian J, Nguyen T, Erikkson C, Wang L, et al. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J Exp Med. 1999;190(7):895-902. 112 Gauvreau GM, O'Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370(22):2102-10. 113 Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA, et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011;12(11):1045-54. 114 Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol. 2012;129(1):191-8 e1-4. 115 Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H. IL-33responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol. 2012;188(3):1503-13.


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134 Grundemann C, Bauer M, Schweier O, von Oppen N, Lassing U, Saudan P, et al. Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. J Immunol. 2006;176(3):1311-5. 135 Trautmann A, Altznauer F, Akdis M, Simon HU, Disch R, Brocker EB, et al. The differential fate of cadherins during T-cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis. J Invest Dermatol. 2001;117(4):927-34. 136 Chu DK, Llop-Guevara A, Walker TD, Flader K, Goncharova S, Boudreau JE, et al. IL33, but not thymic stromal lymphopoietin or IL-25, is central to mite and peanut allergic sensitization. J Allergy Clin Immunol. 2013;131(1):187-200 e1-8. 137 Chu DK, Mohammed-Ali Z, Jimenez-Saiz R, Walker TD, Goncharova S, Llop-Guevara A, et al. T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes. Mucosal Immunol. 2014. 138 Spencer SP, Wilhelm C, Yang Q, Hall JA, Bouladoux N, Boyd A, et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity.

Science. 2014;343(6169):432-7. 139 Dolinay T, Kaminski N, Felgendreher M, Kim HP, Reynolds P, Watkins SC, et al. Gene expression profiling of target genes in ventilator-induced lung injury. Physiol Genomics. 2006;26(1):68-75. 140 Enomoto Y, Orihara K, Takamasu T, Matsuda A, Gon Y, Saito H, et al. Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack. J Allergy Clin Immunol. 2009;124(5):913-20 e1-7. 141 Fukumoto J, Harada C, Kawaguchi T, Suetsugu S, Maeyama T, Inoshima I, et al. Amphiregulin attenuates bleomycin-induced pneumopathy in mice. Am J Physiol Lung

Cell Mol Physiol. 2010;298(2):L131-8. 142 Cook PW, Mattox PA, Keeble WW, Pittelkow MR, Plowman GD, Shoyab M, et al. A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin. Mol Cell Biol. 1991;11(5):2547-57.


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Rag1− /− mice and other T-cell-deficient strains have higher resting ILC2 numbers, perhaps due to the greater basal availability of IL-2 and/or IL-7 [80, 81].

ILC2 express certain characteristic chemokine receptors that play roles in the homeostatic distribution of lymphocytes to specific organ sites [5], most prominently CXC-chemokine receptor 6 (CXCR6), CXCR4, and CC-chemokine receptor 9 (CCR9). CXCR6, also prominently found on both NK and Vα14i-NKT cells, has only one known ligand, CXCL16, and is expressed in the spleen, liver, and lung [82]. CXCR4 has one reported

ligand,

stromal

cell-derived

factor-1

(SDF-1/CXCL12)

[83],

a

B-cell

developmental factor [84, 85] that may also play roles in granuloma formation and type2 cytokine production in the context of S. mansoni antigens [86]. CCR9 binds thymusexpressed cytokine (TECK/CCL25) [87], a chemokine expressed highly in the gut, and important for the homing of intraepithelial lymphoid cells [87-89]. Prostaglandin D2

-

(PGD2) and IL-33 have also been shown to induce human ILC2 migration in a dosedependent manner, with mast cell-derived PGD2 capable of triggering ILC2 through its receptor, CRTH2 [90]. Additionally, ILC2 may express other, tissue-specific homing and retention molecules. Skin ILC2, for example, but not mucosal ILC2, have been found to


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express CD103, the αEβ7 integrin also expressed by other skin-resident leukocyte populations, including T cells [80].

The geographical organisation of ILC2 in the lungs remains largely unknown – recent work suggests that in naive mice, ILC2 are embedded in collagen-rich regions near the intersection of airways and blood vessels but absent from alveoli [91] and that, ILC2 can accumulate in the submucosa around the α-actin smooth muscle layer of the airways upon inhalation of IL-25, IL-33, or ragweed [92].

The interplay of upstream innate signals and ILC2 in asthma and allergic rhinitis Asthma studies have highlighted genes associated with ILC2 [17, 93-95]. Additionally, IL33, IL-25, TSLP and associated receptor transcript and protein levels are elevated in patients with asthma [96-104], allergy [105], and rhinosinusitis [106-108]. Indeed, the neutralisation of IL-25 [10, 109], ST2 [110, 111], or TSLP [112] was able to ameliorate early and late type-2 inflammatory responses in mouse models, and, in the case of TSLP, in human asthmatics. Subsequently, several laboratories have observed ILC2 in murine lungs and draining lymph nodes [76, 77, 113-117] as well as in human airways and nasal polyps [113, 118].


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In mice, the intranasal administration of recombinant IL-25 or IL-33 induces ILC2 expansion in the lungs, bronchoalveolar lavage fluid (BALF) and draining lymph nodes [32, 114, 115] resulting in airway hyperreactivity (AHR) due, in part, to ILC2-produced IL13 [114]. Interestingly, IL-33 appears to be much more potent than IL-25 in recruiting/expanding lung ILC2, and in inducing AHR; IL-33 can even amplify methacholine-induced airway contraction in lung slices ex vivo [92]. The overexpression of TSLP via a surfactant protein C promoter in mice is sufficient to spontaneously produce the major clinical hallmarks of asthma [40], but this process requires antigenic stimulation and CD4+ T cells [119].

Several murine models have demonstrated the critical role of cross-talk between epithelial alarmins and ILC2 in the initiation of type-2 inflammation in the lung. Mice subjected to an ovalbumin-alum model of asthma upregulated IL-25 following ovalbumin challenge [10]. Of more physiological relevance, mouse type-2 pneumocytes have been shown to act as major sources of IL-33 following intranasal exposure to various allergens with IL-33 acting in an auto/paracrine manner [120]. The inhalation of the clinically relevant fungal allergen Alternaria alternata induced IL-33, ILC2 expansion, IL-5 and IL-13 production, and eosinophilia, in wild-type, but not T1/ST2-deficient mice [115].


Lung

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ILC2 have also been implicated in lung fibrosis, with the development of S. mansoni eggassociated pulmonary fibrosis in mice being partially dependent on IL-13 produced by ILC2 in response to IL-25 [121]. Recently, van Dyken et al. also demonstrated that chitininduced eosinophilia required ILC2-derived IL-5 and IL-13, whereas the induction of alternatively activated Mφ (AA Mφ), which are associated with fibrosis, depended exclusively on ILC2-derived IL-13 [122].

Interestingly, these lung ILC2 appeared to

suppress a TH17 cell-associated immune response in this model by an as-yet unidentified mechanism.

Additional cytokines and lipid mediators are also important in the ILC2-mediated pathogenesis of allergic disease. In a papain model of allergic lung inflammation IL-2 and IL-33 were found to induce IL-9, and the neutralisation of IL-9 abrogated ILC2secreted IL-5 and IL-13, suggesting an IL-9 feedback loop that potentiates the ILC2 response [78]. The tumor necrosis factor (TNF) superfamily member TL1A has also been shown to promote ILC2 proliferation, expansion, and production of cytokines through the DR3 receptor [123, 124]. ILC2 numbers were markedly reduced in DR3-knockout mice that were subjected to ovalbumin-alum and papain models of allergic lung inflammation, respectively [123, 124]. Cysteinyl leukotriene receptor 1 (CysLT1R), the high-affinity


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receptor for leukotriene D4 (LTD4), is highly expressed on lung ILC2, and in vitro LTD4 induced ILC2 to rapidly generate high levels of IL-5, IL-13, and IL-4. LTC4, LTD4, and LTE4 administered in vivo rapidly induced IL-5 production from ILC2, and LTD4 could potentiate A. alternata-induced eosinophilia, as well as ILC2 accumulation and proliferation [125].

There continues to be evidence that in addition to the epithelium, other members of the innate immune system engage and depend on ILC2 to enhance the downstream TH2

effector

response.

The

administration

of

Vα14i-NKT

cell-activating

glycosphingolipids [126] or influenza virus [77, 127] have been shown to induce AHR and induce type-2 inflammation by activating Vα14i-NKT cells, which results in IL-33 production by alveolar Mφ, DCs, and type-2 pneumocytes, and, subsequently, ILC2 production of IL-5 and IL-13. Additionally, ILC2 participate in antiviral responses to pneumovirus [128] and neonatal rhinovirus [129], which predispose mice to airway hyperresponsiveness, enhanced type 2 responses and airway remodelling via mechanisms that are, in part, T cell-independent.


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The interplay between upstream innate signals and ILC2 in other allergic diseases Although most studies examining the interaction of type-2-initiating cytokines and ILC2 have focused on the lung, there have been a few reports examining the role of this innate axis in other type-2 diseases, including atopic dermatitis and food allergy.

The skin-selective keratin-14 promotor-driven expression of IL-33 resulted in spontaneous atopic dermatitis (AD)-like erythemas with erosions, exudations, scales, and crusts on the skin. High numbers of infiltrating eosinophils, MCs, TH2 cells and ILC2 were noted, emphasising the link between upstream type-2 cytokines and the resultant type-2 immune response [130]. Roediger et al. observed the presence of ILC2 expressing low levels of CD117 and high levels of CD103 in the skin [80]. These “dermal ILC2” could be tracked by taking advantage of their high levels of expression of CXCR6. Bone marrow chimeras reconstituted with Rag1− /− Cxcr6gfp/+ cells resulted in a fluorescent population of ILC2 that were readily detectable by multiphoton microscopy. Unlike cutaneous T cells, the average speed of ILC2 was characterised by brief migratory periods followed by extended pauses, with a slower average speed similar to dermal DCs. The authors observed sustained stable interactions between ILC2 and skin MCs [80].


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Kim et al. and Salimi et al. concurrently found that ILC2 were resident in human skin biopsies in numbers much greater than the circulating blood. These cells were more numerous and expressed higher levels of IL-17RB, ST2, and TSLPR in the skin of atopic dermatitis patients compared to controls [131, 132]. Another study noted that dermal ILC2 also express the skin-homing marker CLA [133]. Additionally, Salimi et al. observed that allergen challenge could induce ILC2 infiltration and/or expansion in the skin. Atopic and non-atopic individuals were administered house dust mite (HDM) allergen epidermally and then suction blisters were formed over the injection site to sample infiltrating skin cells. IL-4, IL-5, IL-13 and expanded T1/ST2+ ILC2 populations were detected in the blister fluid of allergic donors one day after HDM allergen challenge, but not in non-allergic individuals [132]. Mice treated intradermally with HDM extract or topically with calcipotriol (MC903), a synthetic form of active vitamin D3 that induces ADlike lesions, also showed concomitant increases in skin ILC2 populations. Furthermore, calcipotriol-mediated inflammation was significantly reduced in systems where ILC2 were depleted or absent and in systems where IL-25 or IL-33, and TSLP were neutralised or knocked out [132]. In contrast, Kim et al. found that the calcipotriol model required TSLP and was IL33-independent and that TSLP-elicited ILC2 could recapitulate the observed


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phenotype [131]. This contradiction may be attributable to differences in mouse strain and/or colony hygiene.

KLRG-1, which is highly expressed by ILC2, has been shown to bind to the cell adhesion molecule E-cadherin, which is expressed by Langerhans cells and keratinocytes [134]. In the lesional skin of AD patients, E-cadherin expression is downregulated on the surface of keratinocytes [135]. Incubation of human ILC2 with plate-bound E-cadherin resulted in inhibited proliferation, the down-regulation of GATA3 expression, and reduced IL-5, IL-13, and amphiregulin production. Thus, tissues that express E-cadherin may ameliorate ILC2-mediated type-2 cytokine-driven inflammatory responses, but when E-cadherin is downregulated, for example in AD, unrestrained ILC2 cytokine production may occur [132].

Although

IL-33,

but

not

IL-25

or

TSLP,

has

been

shown

to

mediate

gastrointestinal (GI) sensitization to peanut antigens in a cholera toxin-dependent model, resulting in the expansion of GI ILC2 [136], ILC2 depletion had no effect on anti-peanut IgG1/IgE production, anaphylactic responses, or recall TH2 cytokine production [137]. However, ILC2 depletion significantly impaired post-anaphylaxis allergic eosinophilic


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inflammatory responses, suggesting that ILC2 may play a more limited but still important role in food allergy.

A surprising recent finding was that vitamin A deficiency resulted in reduced ILC3 numbers and, conversely, increased ILC2 and ILC2-derived IL-4, IL-5, and IL-13 in the gut, with similar effects observed in vitro using retinoic acid (RA) inhibitors [138]. Although blocking RA impaired TH2 induction in a Trichuris muris infection model, ILC2 numbers were significantly increased and parasite burdens were controlled comparably to control infected mice. ILC2 may therefore act as sensors of dietary stress and compensate for the collapse of adaptive immunity in these conditions, which may have important implications for the role of diet on the development of allergic responses in the gut.

ILC2-innate system cross-talk in resolution, remodelling, and repair Among the most significantly elevated genes expressed by lung ILC, were multiple genes associated with tissue remodelling, including genes encoding the extracellular matrix proteins decorin, asporin, and dermatopontin, as well as epidermal growth factor family members, most notably, amphiregulin [113]. Amphiregulin was also detected in human ILC2, with higher levels in skin versus blood ILC2 [132].


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Amphiregulin has been implicated in regulating tissue repair and remodelling in the course of acute epithelial injury and asthma [139-141]. Additionally, it plays important roles in wound healing and dermatitis, strongly stimulating keratinocyte proliferation [142-145] and may modulate immune function by enhancing regulatory Tcell (Treg) suppressive functions [146]. Analysis of lung tissue from ILC2-depleted mice infected with influenza virus revealed reduced amphiregulin mRNA, suggesting that lung ILC2 are a primary source of amphiregulin. In these mice, the administration of recombinant amphiregulin promoted the restoration of airway epithelial integrity and tissue homeostasis [113]. IL-9R-deficient mice exhibited reduced lung ILC2 numbers after

N. brasiliensis infection, resulting in decreases in IL-5, IL-13, and amphiregulin. Subsequent tissue repair and lung function were strongly impaired in the absence of IL-9 signalling, in part due to the reduced expression of amphiregulin and increased apoptosis of ILC2 [147].

The interplay between ILC2 and downstream type-2 effectors: a quicksilver messenger service? Although evidence is mounting that the epithelial cell-ILC2 axis plays important roles in the initiation and regulation of various type-2 immune conditions, it is by no


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means the only critical aspect. DCs, TH2 cells, and B cells are prominent players in the pathogenesis of allergy and asthma and direct the adaptive arm of the allergic response.

In tissues such as the skin and lung, DCs integrate cues derived from allergens and inflammatory environmental contexts. By processing, transporting, and presenting protein antigens, DCs are able to activate antigen-specific naïve T cells in draining lymphatics. Several mechanisms have been proposed to explain how DCs initiate TH2-cell differentiation, including TCR signal strength, the presence of cytokines such as IL-2 and IL-4, and interactions with certain costimulatory molecules including CD40L and OX40L [43, 148-151].

Additionally, DCs have been shown to play roles in maintaining

inflammatory responses [152]. Indeed, allergic sensitization in murine lungs [153] and skin [154] as well as robust immune responses to helminths [155] require tissue-resident DCs.

An open question remains as to whether ILC2 may also play a role in antigen presentation, TH2 polarization, and memory recall responses. Recent reports provide the first evidence that ILC2 may in fact play a critical role in the DC-T-cell arm of allergic inflammation. When RORα-deficient staggerer (Rorasg/sg) bone marrow-transplanted


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(BMT) mice, which are specifically deficient for ILC2, were subjected to a papain model of allergic airway inflammation, both the early innate and late-phase TH2-mediated eosinophilia and IgE responses were abrogated, suggesting a palpable role for ILC2 in modulating type-2 adaptive immunity [156]. IL-4 was found to be dispensable in this model, consistent with previous reports [157, 158], but IL-13 produced by ILC2 was required. The adaptive type-2 immune response to papain and co-administered ovalbumin in BMT mice was restored by wild-type, but not il13− /− ILC2, and IL-13 was found to induce the efficient migration of activated DCs to draining lymph nodes. This was mediated in part through the prostaglandin (PG)E2-EP4 pathway, which has been shown to be required for the sensitisation of CCR7+ DCs to a CCL21 gradient [159-161].

In addition to IL-13, ILC2 may initiate and support TH2 differentiation through other means, including the production of critical activating cytokines such as IL-6 [162]. One intriguing possibility is that ILC2 may interact with CD4+ T cells via TCR-major histocompatibility complex class II (MHCII) interactions. MHCII is expressed on the surface of ILC2 and ILC3 [5, 78, 163, 164].

ILC3 expressing MHCII in the absence of

CD80/86 co-stimulation have been reported to induce the suppression of immune responses to commensal bacteria in the gut [164]. Recently, ILC2 have been shown to


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potentially act as antigen-presenting cells (APCs), driving ovalbumin-specific DO11.10 transgenic T-cell proliferation in vitro and preferentially inducing TH2-cell differentiation [165]. Notably, this effect was observed when ILC2 were pulsed with OVA peptide but not whole protein, which suggests ILC2 may acquire exogenous peptides in a manner different from DCs. Indeed, type-2 immune response-associated antigens released by helminths [166] and allergens (e.g., Der p 1 and papain) [76, 167] often have protease activity, which may produce a ready-made source of peptides.

The interplay between ILC2 and B cells has yet to be fully described, though a recent report on interactions between splenic ILC3 and marginal zone (MZ) B cells [168] supports speculation in this area. Indeed, ILC2 in fat-associated lymphoid clusters (FALC) promoted IgA production and induced the division of innate B-1 cells [6]. As potent sources of IL-5 and IL-6, which induce IgA class-switching [169, 170] and serve as important B-cell growth and maturation factors [171, 172], ILC2 may help direct other type-2 B-cell responses.

Notably, one of the characteristic markers of ILC2 is the co-

stimulatory molecule ICOS, which can engage ICOS-L on B cells inducing the production of cytokines such as IL-2, IL-4, and especially IL-10 [173] and is important in germinalcentre responses and class switching [174, 175].


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Conclusions and Future Directions: shooting the messenger With the discovery of ILC2 our understanding of the initiation, regulation, and maintenance of type-2 inflammation has changed remarkably.

ILC2 serve as a critical

link between the production of IL-25, IL-33 and TSLP by helminth- and allergendamaged epithelium and the development of long-lasting and often debilitating type-2mediated conditions (Figure 1). Significant progress has already been made identifying ILC2 in a variety of human allergic diseases, and knock-out and replacement experiments in mice have revealed how important their potent armament of cytokines, especially IL-5, IL-9, and IL-13 are in the propagation of many innate allergic responses.

Our

understanding of ILC2-interaction partners and the parts played by ILC2 in antigen presentation, recall responses, and T- and B-cell memory are still in their infancy and will be accelerated by the development of ILC2-specific deletion strategies, more extensive imaging studies, and a finer grasp of ILC2 homeostasis and trafficking. Emerging studies suggest that ILC2 are more than mere messengers, translating upstream cytokine signals into downstream ones, but rather, like the mythological figure Mercury, hidden for too long, they quickly shuttle between worlds acting as both emissary and intercessor. Thus, ILC2 appear to interact at multiple levels in the type-2 immune response, and our challenge is to target their interplay for potential therapeutic benefit.


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Accepted Article

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Accepted Article

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Accepted Article

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Accepted Article

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Accepted Article

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Accepted Article

Figure Legend Figure 1. ILC2 are central players in type-2 inflammatory responses. Interactions with helminths and allergens induce epithelial cell damage and lead to the production of IL25, IL-33, TSLP, and TL1A, which, in combination with IL-2 and/or IL-7, activate ILC2, whereupon they secrete various type 2 cytokines including IL-5 (eosinophil proliferation), IL-6 (B cell growth factor), IL-9 (mast cell growth factor, autocrine ILC2 expansion), and IL-13 (AHR, mucus production, smooth muscle contractility, alternative activation of macrophages and airway remodelling). ILC2 may play a role in wound healing and remodelling through the production of amphiregulin (AREG). Additionally ILC2 may influence the adaptive TH2 response by directing DC trafficking into the draining lymph node (LN) via IL-13-mediated upregulation of CCR7, and by its ability to possibly uptake antigens and present them to naïve T cells via MHC II. Abbreviations: group-2 innate lymphoid cell (ILC2), T helper cell (TH), B cell (B) dendritic cell (DC), mast cell (MC), eosinophil (Eo), alternately activated macrophage (aaMφ), amphiregulin (AREG), major histocompatibility complex II (MHCII), T-cell receptor (TCR).


Accepted Article This article is protected by copyright. All rights reserved.

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