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REVIEW ARTICLE Orchestration between and Th2 cells in shaping type 2 immune responses

Rama Krishna Gurram1 and Jinfang Zhu1

The type 2 immune response is critical for host defense against large parasites such as helminths. On the other hand, dysregulation of the type 2 immune response may cause immunopathological conditions, including , , rhinitis, and anaphylaxis. Thus, a balanced type 2 immune response must be achieved to mount effective protection against invading pathogens while avoiding immunopathology. The classical model of type 2 immunity mainly involves the differentiation of type 2 T helper (Th2) cells and the production of distinct type 2 , including -4 (IL-4), IL-5, and IL-13. Group 2 innate lymphoid cells (ILC2s) were recently recognized as another important source of type 2 cytokines. Although , mast cells, and can also express type 2 cytokines and participate in type 2 immune responses to various degrees, the production of type 2 cytokines by the lymphoid lineages, Th2 cells, and ILC2s in particular is the central event during the type 2 immune response. In this review, we discuss recent advances in our understanding of how ILC2s and Th2 cells orchestrate type 2 immune responses through direct and indirect interactions.

Keywords: Type 2 immune response; type 2 (Th2); Group 2 (ILC2); and asthma

Cellular & Molecular Immunology (2019) 16:225–235; https://doi.org/10.1038/s41423-019-0210-8

INTRODUCTION eosinophils from into the tissue, leading to The type 2 immune response is mediated by various cytokines eosinophilic airway inflammation. IL-9 causes mast cell activation. that regulate diverse cellular functions, ranging from anti- IL-13 induces hyperplasia, hypersecretion and helminth parasite immunity to allergic inflammation, wound hyperreactivity. healing, and .1–6 A diverse variety of compounds, The traditional perception of type 2 immune responses is including macroscopic helminth worms, microscopic particles and largely focused on the generation of Th2 cells (Fig. 1). In this soluble enzymes, can elicit type 2 immune responses, which are model, antigen is taken up by specialized DCs, which then migrate orchestrated by several cell types.7 However, in this review, we will to local draining lymph nodes, where these DCs activate and mainly discuss the two major players in type 2 immune responses, instruct naïve CD4+ T cells to become Th2 cells. Differentiated Th2 namely, type 2 T helper (Th2) cells and group 2 innate lymphoid cells then egress from the lymph nodes and enter into the tissue, cells (ILC2s). where they produce effector cytokines IL-4, IL-5, and IL-13.11,12 The type 2 immune response often causes recruit- However, this model cannot rationalize a rapid induction of the ment to inflamed sites, which is one of the characteristic features type 2 immune response in RAG-deficient mice, in which T cells of type 2 immunopathologies, including asthma, rhinitis, atopic are absent. dermatitis, and anaphylaxis.8,9 In addition to eosinophilia, such In recent years, it has become clear that, in addition to adaptive responses also include basophilia and the recruitment of mast lymphoid cells, there are -like innate cells that play cells and alternatively activated M2 . Asthma is the important roles in immunity and inflammation. These cells are one of the most prevalent type 2 immunopathologies. The clinical now designated as ILCs and are also considered the innate feature of asthma is airway obstruction, which directly results from counterparts of adaptive T helper cells. These cells can be the inflammation of airway mucosa-associated tissue. The type 2 classified into group 1 ILCs (ILC1s), which produce IFN-γ and immune response is elicited by the concatenated events enforced depend on the T-bet for their development; by type 2 cytokines, including IL-4, IL-5, IL-9, and IL-13. IL-4 induces group 2 ILCs (ILC2s), which produce IL-5, IL-13, and IL-9 IgE production; then, IgE along with antigen forms immune and require GATA3; and group 3 ILCs (ILC3s), which mainly complexes that bind to high-affinity IgE receptors (FcεR1) on produce IL-22 and IL-17A and need RORγt for their development basophils and mast cells, causing the degranulation and release of and function.13–17 several proinflammatory mediators, such as histamine, heparin, In the context of type 2 immune responses, the discovery of and serotonin,10 which in turn are responsible for the immediate ILC2s has expanded our understanding from the classical DC-Th2- symptoms of the acute allergic response, including bronchocon- centric view to an ILC2-DC-Th2 axis (Fig. 2). In this new striction. IL-5 is responsible for the activation and recruitment of model, ILC2s are activated by -derived cytokines,

1Molecular and Cellular Immunoregulation Section, Laboratory of Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA Correspondence: Rama Krishna Gurram ([email protected]) or Jinfang Zhu ([email protected]) Received: 30 November 2018 Accepted: 31 January 2019 Published online: 21 February 2019

© CSI and USTC 2019 Orchestration between ILC2s and Th2 cells in shaping type 2 immune. . . RK Gurram and J Zhu 226 , and helminths. The first step in the initiation of the type 2 immune response occurs when the products of or helminths are sensed. Compared to bacterial and viral products, the immune initiation signals triggering a type 2 immune response are more complex, ranging from macroscopic helminths to microscopic particles, including chitins, pollens, house dust mites, and soluble enzymes (e.g., proteases). Upon exposure to helminth parasites or allergens, epithelial cells produce a variety of cytokines, including IL-1α, IL-33, IL-25, GM-CSF, and TSLP, and inflammatory mediators such as uric acid and ATP. Type 2 immunity requires the complex coordination of multiple cell types at the epithelial barrier. In response to type 2 stimuli, epithelial cells can also express , including CCL17, CCL22, and eotaxins (CCL11, CCL24, and CCL26), leading to the recruitment of DCs, eosinophils, basophils, mast cells, and Th2 cells.24 Epithelial cells also express a set of cytokines that educate DCs in promoting adaptive Th2 cell immunity and activate ILC2s, basophils, eosinophils, and mast cells.20,25–27 DCs exposed to IL-33 may promote the differentiation of IL-5- and IL-13-producing T helper cells from naïve CD4 T cells; the adoptive transfer of IL-33- treated DCs into naïve mice enhances lung airway inflammation.28 Fig. 1 Classic model of a type 2 immune response. In allergic Furthermore, TSLP induces OX40 ligand (OX40L) expression on asthma or during helminth infection, an or a helminthic DCs, and OX40L expressed on activated DCs induces Th2 cell antigen is phagocytosed by dendritic cells, which then migrate to 29 + differentiation. the draining , where naïve CD4 T cells recognize the In addition to the alarmins, epithelial cells also produce danger- processed antigen presented by the peptide-MHC-II complex along associated molecular patterns (e.g., ATP and uric acid) upon with costimulatory molecules. After recognition of antigen pre- sented by dendritic cells (DCs), naïve CD4+ T cells differentiate into exposure to allergen. Both humans and mice were shown to

1234567890();,: effector Th2 cells. Th2 cells migrate into the site of inflammation and release ATP and uric acid in bronchoalveolar lavage upon 30,31 produce Th2 cytokines such as IL-5, which is responsible for exposure to HDM, which plays a crucial role in the induction eosinophilia, and IL-13, which promotes mucus production and of IL-25, IL-33, and TSLP secretion by epithelial cells. Furthermore, goblet cell hyperplasia. Th2 cells also produce IL-4, which is involved in response to ATP released from apoptotic epithelial cells after in antibody class switching and the production of IgE worm infection, mast cells may also produce IL-33 and thus are involved in the initiation of type 2 responses.32 Interestingly, IL-25 is constitutively expressed by tuft cells in the gut and is important including IL-33, IL-25, and thymic stromal lymphopoietin (TSLP).18 for maintaining ILC2 .33–35 During a type 2 immune These molecules elicit the production of type 2 cytokines by ILC2s. response, IL-25 induces IL-13 production by ILC2s, and IL-13 Interestingly, ILC2s constitutively express certain levels of IL-5, produced by ILC2s and/or Th2 cells can promote the differentia- even in steady state, while IL-13 production is induced during type tion and expansion of tuft cells, resulting in a positive feedback 2inflammation.19 Although ILC2s mainly express IL-5 and IL-13, loop.33 The type 2 immune response also involves other cells, some ILC2s may express low levels of IL-4 under certain including alternatively activated M2 macrophages. The release of circumstances.20,21 In fact, IL-4 production by ILC2s may promote pro-inflammatory mediators by these cells is critical for expelling food allergy22 and induce Th2 cell differentiation during worm helminth parasites, although this process also causes significant infection.23 Type 2 cytokines secreted by either ILC2s or Th2 cells tissue damage and altered tissue function.4,36 (or both) result in the recruitment and activation of granulocytes, Many cysteine proteases, such as papain and Der p1, from the including eosinophils, mast cells, and basophils. Thus, both ILC2s HDM species D. pteronyssinus induce type 2 responses through and Th2 cells can induce type 2 immune pathology by releasing disruption of the epithelial cell barrier via their proteolytic type 2 effector cytokines. activity37. In addition to disrupting the epithelial cell barrier, these In this review, we summarize recent advances in studying the proteases can also activate respiratory epithelial cells by cleaving relative contributions of the innate and adaptive arms of the protease activated receptor 2 (PAR2) on the cell surface,38,28. Many immune system during type 2 immune responses. We begin with allergens with serine protease activity, including trypsin, also a discussion of epithelial cells as a hub for the initiation of type 2 depend on the activation of PAR2 to induce allergic responses.39,40 immune responses, how the immune system senses a diversity of Some reports suggest that low levels of lipopolysaccharide (LPS) allergens, and how tissue-derived signals are crucial for activating induce Th2 responses, and the allergenicity of certain allergens and inducing ILC2s and Th2 cells. Second, we focus on how Th2- such as house dust mite (HDM) relies on Toll-like receptor (TLR) and ILC2-mediated immune responses are initiated and orche- 4.41,42 It is also reported that most aerosol allergens, including strated. Third, we discuss how ILC2s modulate the type 2 immune HDM and chitin from cockroach exoskeleton, are usually response via regulating Th2 cell activation and function. Finally, contaminated with minute levels of LPS.43 Similar to antigen- we conclude by highlighting some key questions to enhance our presenting cells, epithelial cells also express TLRs.44,45 Triggering understanding of type 2 immune responses. TLR activation on epithelial cells results in the production of several cytokines, including IL-1α, TSLP, IL-25, and IL-33 (Fig. 2).46,47 The release of IL-1α induced by HDM is considered to occur TYPE 2 IMMUNE RESPONSE INITIATED BY EPITHELIAL CELLS upstream of the secretion cascade. The IL-1α released by The epithelial cell barrier not only represents the first line of epithelial cells acts in an autocrine manner to trigger the release of defense against invading pathogens but also provides instructive GM-CSF and IL-33.47 These cytokines in turn cause the cascade of signals that program DCs and Th2 cells (and/or ILC2s) to mount allergic events via activation of mucosal DCs and tissue-resident type 2 immune responses. The mucosal resident epithelial cells ILC2s. Interestingly, TLR4 expressed by lung epithelial cells but not function as specialized tissue sentinels to detect a broad array DCs is necessary and sufficient for HDM-induced DC activation of stimuli, including allergens and pathogens, such as , and Th2 cell differentiation.46

Cellular & Molecular Immunology (2019) 16:225 – 235 Orchestration between ILC2s and Th2 cells in shaping type 2 immune. . . RK Gurram and J Zhu 227

Fig. 2 Type 2 immune response from the perspective of the ILC2-DC-Th2 cell-centric axis. Pathogen sensing or tissue damaging signals induced by exposure to helminth infection or protease allergen result in the secretion of alarmins, such as IL-25, IL-33, and TSLP. ATP released from epithelial cells may also induce mast cells to produce IL-33. These alarmin cytokines activate ILC2s, resulting in the production of the type 2 cytokines IL-4, IL-5, IL-9 and IL-13. The neuropeptide neuromedin U (NMU) can also activate ILC2s. The type 2 cytokines secreted by ILC2s may support the differentiation of naïve CD4 T cells into effector Th2 cells. Additionally, DCs receive signals from IL-13 secreted by ILC2s and TSLP released by epithelial cells during pathogen sensing and become capable of inducing effector Th2 cell differentiation from the naïve CD4 population. IL-9 produced by ILC2s may act on these ILC2s to promote cell expansion as well as recruit mast cells. Overall, the type 2 cytokines secreted by ILC2s and Th2 cells, especially IL-5 and IL-13, cumulatively contribute to type 2 immunopathology

The epithelial barrier surfaces, including , gut and the infection, which has been highlighted in models in which subset- airway, are densely populated by neurons, and crosstalk between specific depletion of DCs diminished the type 2 immune response the nervous system and several immune cells has been recently to helminths and allergens.59–61 reported.48–50 Likewise, ILC2s also respond to the signals mediated Th2 cells exert their functions through the production of various by the nervous system at the epithelial barrier. ILC2s express type 2 effector cytokines, including IL-4, IL-5, IL-9, and IL-13. neuromedin U receptor 1 (Nmur1) on their surface, and the Initially, IL-4 secreted by Th2 cells was thought to be important for nervous system regulates ILC2 activation via neuromedin U (NMU) regulating the class switch recombination of B cells to produce secretion.51,52 Coordinated neuron-ILC2 crosstalk contributes to IgE. However, follicular T helper (Tfh) cells can also express IL-4 protective immunity and worm expulsion. Furthermore, ILC2s and thus may regulate the IgE response.62,63 Nevertheless, the role express β2-adrenergic receptor (β2AR), which interacts with the of Tfh cells in the development of type 2 immunity remains neurotransmitter epinephrine. In contrast to NMU, β2AR agonists ambiguous. Some recent literature demonstrated that Tfh cells diminish the ILC2-mediated immune response, indicating that the may contribute to type 2 immunity by serving as the precursors of β2AR signaling pathway negatively regulates ILC2 activity.53 effector Th2 cells.64 HDM challenge causes some Tfh cells to differentiate into IL-4 and IL-13 double-producing Th2 cells that accumulate in the lung and cause pathology. Furthermore, IL-21 TYPE 2 IMMUNE RESPONSE MEDIATED BY TH2 CELLS secretion by T cells promotes the generation of effector Th2 An important component of the type 2 immune response is the cells.65 As mentioned earlier, IgE cross-linking with high-affinity Fc process by which antigen-specific naïve CD4 T cells differentiate receptors for IgE (FcεR1) on granulocytes, including basophils and into Th2 cells. DCs residing at the antigen-exposed area first take mast cells, results in their degranulation. IL-5 secreted by Th2 up antigens, process them, and then present them via major cells causes the recruitment and expansion of eosinophils from histocompatibility complex (MHC) class II (MHCII) molecules. Next, bone marrow.66 Furthermore, IL-4 and IL-13 secreted by Th2 DCs migrate to the draining lymph nodes, where a small number cells may play indirect roles in eosinophilia in mucosal tissue by of antigen-specific naïve CD4 T cells encounter the DCs through T upregulating eotaxin-1 (CCL11) and eotaxin-3 (CCL26) expression cell receptor (TCR)/peptide-MHCII interactions in the presence of by epithelial cells.67 IL-13 can also induce smooth muscle costimulatory molecules and cytokines and become activated. movement, goblet cell hyperplasia, subepithelial fibrosis, and These activated CD4 T cells proliferate and differentiate into mucus hypersecretion.68 effector Th2 cells before they migrate into sites of inflammation.11 The cytokine environment plays a crucial role during the differentiation of Th subsets.54,55 Thus, IL-4 is involved in Th2 cell TYPE 2 IMMUNE RESPONSE MEDIATED BY ILC2S differentiation.56,57 IL-4-mediated STAT6 phosphorylation is essen- Th2 cells were thought to be the characteristic hallmark feature of tial for the generation of Th2 cells, particularly in vitro.58 However, type 2 immunity; however, the discovery of ILC2s challenged this IL-4-independent Th2 cell differentiation has been observed simple view. In fact, RAG-deficient mice, in which both T cells and in vivo.7 DCs are essential for the differentiation of naïve CD4 B cells are absent, are still able to produce IL-5 and IL-13 in T cells into Th2 cells in response to allergen exposure or helminth response to IL-25 treatment, and the induction of these cytokines

Cellular & Molecular Immunology (2019) 16:225 – 235 Orchestration between ILC2s and Th2 cells in shaping type 2 immune. . . RK Gurram and J Zhu 228 may result in type 2-like immunopathology, including eosinophi- that are critical for their distinct phenotypes and functions. lia, epithelial cell hyperplasia, and increased mucus production, in However, many of these transcription factors may be expressed the absence of Th2 cells.69 Such IL-5 and IL-13 production in transiently or at low levels in different ILCs. For example, all ILC response to IL-25 treatment is derives from c-Kit-expressing cells subsets express low levels of GATA3, and its expression is that are negative for T cell marker, marker, and FcεR1.20 This functionally important during the development and maturation novel lymphoid cell population, now known as ILC2, is actually of different ILC subsets.83,102,103 Recent literature indicates that also one of the main sources of type 2 cytokines during N. environmental cues can elicit the phenotypic heterogenicity and brasiliensis infection. This also explains why IL-4 and IL-13 functional plasticity of these cells. For example, RORγt+ ILC3s production by Th2 cells is not essential for protective immunity exposed to IL-12, IL-15, and/or IL-23 may upregulate IFN-γ and again N. brasiliensis.15 In addition, intranasal administration of T-bet expression to become ILC1-like cells.104,105 Interestingly, papain rapidly induces lung eosinophilia and mucus hyperpro- even in the steady state, NKp46+ ILC3s co-express T-bet and duction in RAG-deficient mice, which are mediated by IL-5 and IL- RORγt.106 Thus, co-expression of multiple transcription factors may 13 produced by lung ILC2s.26 Thus, ILC2s are a major source of enable the plasticity and heterogeneity of ILCs in response to type 2 cytokines during allergic lung inflammation and parasitic various stimuli. helminth infection, and these cells may elicit a type 2 immune Recent evidence indicates that ILC2s exhibit a certain degree of response even in the absence of the . heterogeneity and plasticity as well. ILC2s found in different Importantly, increased ILC2 cell numbers are also associated with tissues express different sets of cytokine receptors and respond to many type 2 diseases in humans.70–73 selective inflammatory cytokines.107 ILC2s found in lung and fat ILC2s express CD127 (IL7Rα), T1/ST2 (IL33R), CD25 (IL-2Rα), tissues mainly express IL-33 receptor, while ILC2s in the gut largely CD90.2 (Thy1), KLRG1, and ICOS.74,75 While ILC2s are thought express IL-25 receptor; strikingly, ILC2s found in the skin express develop mainly in the bone marrow, they may also develop in the functional IL-18 receptor but not IL-25 or IL-33 receptors.107,108 and/or in tissue.76–78 The development of ILC2s critically This explains why ILC2-dependent atopic dermatitis may occur in depends on several important transcription factors, including an IL-33-independent manner.89 It has been found that mice inhibitor of DNA binding 2 (Id2), RORα, and GATA3.79–86 Like Th2 systemically injected with IL-25 generate inflammatory ILC2s cells, ILC2s are capable of producing type 2 cytokines, especially (iILC2s). These iILC2s may co-express IL-13 and IL-17 under certain IL-5 and IL-13. ILC2s do not express receptors for antigens. Instead, conditions.109 It has also been reported that exposure of ILC2s to as mentioned earlier, they mainly respond to cytokines, including IL-25 and Notch ligand induces the upregulation of transcription IL-33, IL-25, and TSLP,13,14 that are rapidly released by epithelial factor RORγt, and these cells may co-express IL-13 and IL-17.110 cells upon damage because most ILC2s express T1/ST2 (an IL-33 Interestingly, IL-17-producing ILC2s play a pathogenic role in a receptor subunit), IL-17RB (a receptor for IL-25), and TSLPR.87–89 mouse model of lung allergy.111 At the molecular level, the Exposure of ILC2s to epithelial-cell-derived cytokines induces ILC2 transcription factors Bcl11b and Gfi-1 regulate the identity of ILC2s activation as well as the production of type 2 cytokines. by repressing the expression of RORγt and its associated genes. Early studies demonstrated that ILC2 proliferation can be Therefore, deletion of Bcl11b or Gfi-1 in ILC2s results in IL-17 enhanced by cytokines, such as IL-2 and IL-7, which signal through production and loss of GATA3, IL-5, and IL-13 expression.112,113 the common γ receptor.14,15 Bone marrow stromal cells, dendritic Some reports also indicate the plasticity of ILC2s, allowing them cells and epithelial cells are the main sources of IL-7. CD4 T cells are to become ILC1-like cells. ILC2s that have experienced a type 1 the major source of IL-2. Indeed, T cells collaborate with ILC2s to proinflammatory milieu may upregulate T-bet and IL-12R; both maintain M2 macrophages during worm infection, presumably human and mouse ILC2s have been shown to upregulate IFN-γ through IL-2 secretion.90 Interestingly, IL-2 produced by ILC3s may expression in an IL-12-IL-12R-dependent manner.114 In addition, also play an important role in the activation of ILC2s in RAG-deficient IL-1β upregulates IL-12Rβ2 expression on ILC2s, which potentiates animals.91 Since IL-4 also uses the common γ chain, its functions in the ILC1 phenotype conversion in response to IL-12.115 The regulating ILC2-mediated immunity were studied. Mice acutely importance of IL-12-IL-12R signaling in the conversion of ILC2s to challenged with papain induce IL-4 production from basophils, ILC1s has been further confirmed through an analysis of patients which in turn regulates ILC2-mediated lung inflammation.92 ILC2s suffering from chronic obstructive pulmonary disease (COPD)116; can also express low amounts of IL-4 during helminth infection, disease severity in these patients is significantly associated with an raising the possibility that IL-4 secreted by ILC2s might serve as an altered ILC1/ILC2 ratio and the frequency of ILC1s. During initial source of IL-4 in inducing Th2 cell differentiation.93 influenza infection, ILC2s can also be activated, although at a late Another cytokine utilizing the common γ receptor for its stage.117 However, whether some of these ILC2s will display a signaling is IL-9. Interestingly, ILC2s themselves may transiently partial ILC1-like phenotype and whether conversion of some ILC2s upregulate IL-9 expression during papain-induced lung inflamma- to ILC1s has occurred in this infection setting is unknown. tion. The results obtained from IL-9-fate mapping mice demon- strate that IL-9 production in papain-induced allergy is restricted to ILC2s.94 Although IL-9 expression by ILC2s is transient, IL-9 plays SIMILARITIES AND DIFFERENCES BETWEEN TH2 CELLS AND a very important role in the activation and survival of ILC2s. ILC2S Neutralization of IL-9 results in reduced levels of IL-5 and IL-13 and Both ILC2s and Th2 cells can efficiently regulate the type 2 thus a reduced type 2 immune response. The autocrine activity of immune response by producing similar sets of type 2 cytokines. IL-9 on ILC2s may also be involved in the differentiation and Although Th2 cells can respond to antigen stimulation, both functions of Th2 cells. Additionally, IL-9 regulates Th2 cells and ILC2s can respond to inflammatory cytokines such as secretion by ILC2s, which plays an important role in tissue repair IL-33 to produce their effector cytokines, as discussed above. during lung inflammation.95–97 In addition to cytokines, the Furthermore, a recent study has shown that IL-33/IL-25/TSLP neuropeptide neuromedin U, leukotrienes, and signaling in differentiated Th2 cells after their migration to the the TNF family member TL1A can promote ILC2 activation and lung tissue is necessary for these cells to gain effector functions, lung inflammation.51,52,98–101 even in response to antigens.118 Not only do activated ILC2s and differentiated Th2 cells display very similar transcriptomes, but epigenetic status at the key regulatory elements of the effector- HETEROGENEITY AND PLASTICITY OF ILC2S associated genes is also remarkably identical.119 Thus, ILC2s The classic view of innate lymphoid cells is characterized by the are considered the innate counterpart of the Th2 effector cell expression of a unique master transcription factor and cytokines subset.119–122

Cellular & Molecular Immunology (2019) 16:225 – 235 Orchestration between ILC2s and Th2 cells in shaping type 2 immune. . . RK Gurram and J Zhu 229 Mice deficient in the expression of the transcriptional regulator GATA3 in both cell types.83,136,142 Moreover, memory Th2 cells Id2 lack all ILC lineages,82 whereas the development of T cells is may upregulate T1/ST2 expression in response to IL-33 in addition largely unaffected. Like other ILCs, ILC2s may develop from to inducing the expression of type 2 cytokines.143 Furthermore, common progenitors that reside in fetal liver, fetal gut, adult bone signaling via T1/ST2 in T cells provides posttranscriptional stability marrow, or peripheral .77,78,84,123–126 After their develop- of the cytokine transcripts.144 The deletion of IL-33 or T1/ST2 ment, ILC2s reside in different tissues, including lung, gut, skin and results in impaired eosinophilic airway inflammation driven by fat tissues, and are present even in naïve mice. By contrast, memory Th2 cells. effector Th2 cells are very rare in naïve animals but develop from activated naïve CD4 T cells during a type 2 immune response after encountering the cognate antigen.127,128 Thus, Th2 cell differ- TH2 IMMUNE RESPONSE MAY BE INITIATED BY ILC2S entiation requires MHCII-antigen recognition; however, ILC2 ILC2s directly contribute to type 2 immunopathology as discussed development is independent of MHCII. Because ILC2s are above; however, ILC2s may also orchestrate an adaptive Th2 predeveloped and tissue-resident cells, they can respond rapidly response under certain circumstances (Fig. 3). Some reports to infection and thus provide the first line of host defense. While suggest that Th2 cell differentiation can be initiated by ILC2s, ILC2s are largely tissue-resident,129 recent studies by Huang et al. particularly because ILC2s are activated during the early phase of show that IL-25 preferentially acts on inflammatory ILC2s in the type 2 immune responses.93,145 The importance of ILC2s in gut, which can migrate to the lung tissue and actively participate regulating the Th2 response has been demonstrated by studies in the expulsion of helminth parasites.109,130 using ILC2 depletion.93,146 Cooperation between ILC2s and Th2 After exposure to allergens, allergen-specific naïve CD4 T cells cells has also been studied by the adoptive transfer of these cells undergo activation and differentiate into effector Th2 cells. Later, into IL-7ra KO mice. Cotransfer of both cell types elicits a robust the effector Th2 cells undergo contraction while leaving some antigen-specific type 2 immune response; however, such a long-lived memory T cells. Upon re-exposure to the same allergen, response is not observed in mice receiving these cells separately. memory Th2 cells respond rapidly and produce type 2 cytokines. Thus, ILC2s seem to regulate Th2 cell differentiation.146,147 Similar to Th2 cells, some activated ILC2s may persist long after Furthermore, IL-13 secreted by ILC2s promotes the activation the resolution of inflammation. These ILC2s respond more and migration of lung dendritic cells into the draining lymph potently than naïve ILC2s after exposure to allergens.131 Thus, node, where they prime naïve CD4 T cells to differentiate into Th2 both Th2 cells and ILC2s have memory, although memory ILC2s cells,145,55,148 However, this is not always the case, since Locksley do not have antigen specificity. and his colleagues have reported that Th2 cell differentiation in Despite several differences, both ILC2s and Th2 cells can be draining lymph nodes occurs normally during Nippostrongylus activated by cytokines, such as IL-33, IL-25, and TSLP. Furthermore, brasiliensis infection in animals that are supposed to be devoid of both ILC2s and Th2 cells are regulated by costimulatory ICOS ILC2s.118 signaling. ILC2s express both ICOS and ICOS-L on their surface, ILC2-T cell interactions may be required to generate an effective and deletion of ICOS results in reduced ILC2 expansion and IL-33- Th2 cell response. Although ILC2s are considered the counterpart induced bronchial inflammation.132 Similarly, ligation of ICOS is of Th2 cells, some ILC2s can express MHC-II molecules, which crucial for the activation of CD4 T cells, Th2 cell differentiation and allow ILC2s to directly modulate the CD4 T cell response.93,149 lung inflammation.133–135 The secretion of type 2 cytokines, While ILC2s do not express TLRs in most cases, they may be including IL-5 and IL-13, by both ILC2s and Th2 cells depends activated by IL-33, as discussed above. Antigen-specific interac- on the master transcription factor GATA-3.83,122,136,137 tions between ILC2s and T cells through MHCII and TCR expressed on these cells, respectively, may contribute to CD4 T cell activation, differentiation and expansion.93,146 In addition to INNATE FUNCTIONS OF TH2 CELLS MHCII-TCR-mediated activation of T cells, the interaction between Following pathogen clearance or disappearance of allergens, ILC2s and Th2 (or uncommitted T) cells through costimulatory antigen-specific effector T cells as well as memory T cells either molecules may also play an important role during type 2 immune enter the circulation or reside in the tissue.138 Upon re-exposure to responses (Fig. 4). The costimulatory molecules CD80 and CD86, in the same antigen, these memory T cells rapidly expand and combination with MHCII, induce ILC2-mediated T cell activation. produce effector cytokines. It has been long assumed that the Indeed, ILC2s express CD80, CD86, ICOS, and OX40L on their TCR-MHCII interaction alone is sufficient for surface, and activated T cells express receptors to these reactivation and effector function.139 Although the expansion ligands.93,132,150 In some cases, the ILC2-CD4 T cell interaction is and functions of effector and memory T cells are regulated by essential for ILC2s to exert an effector response. The importance of antigen-specific TCRs that recognize peptide presented by ILC2-CD4 T cell interactions was demonstrated by infecting IL-13- antigen-presenting cells in the context of MHCII, T cell effector deficient mice reconstituted with either wild-type or MHCII- function can also be elicited by noncognate stimuli. Indeed, an deficient ILC2s with N. brasiliensis. Strikingly, N. brasiliensis was inflammatory environment promotes noncognate stimulation of expelled by the mice that had received wild-type ILC2s, however, CD4 T cells, and differentiated CD4 T cells can also be activated by mice that received MHCII-deficient ILC2s still showed impaired innate cytokines.140 In some cases, polyclonal Th2 cells can worm clearance.93 The ILC2-CD4 T cell interaction may lead to IL-2 directly respond to the innate cytokine IL-33, just as ILC2s, and secretion by CD4 T cells, which promotes a local type 2 response contribute to the pathogenicity of allergic disease by secreting IL- by activating ILC2s. 5 and IL-13.141 The noncognate activation of CD4 T cells may The ligation of OX40 ligand (OX40L) expressed on ILC2s with contribute to allergic inflammation and protection against OX40 expressed on CD4 T cells is essential for the type 2 immune parasitic infection in an antigen/allergen-independent manner. response.147 Expression of OX40L on ILC2s can be upregulated During a type 2 immune response, IL-33, a member of the IL-1 upon exposure to IL-33, and ILC2-specific deletion of OX40L family of cytokines, may stimulate Th2 cells to produce type 2 significantly affects the responses of Th2 cells and regulatory effector cytokines.27,141 Thus, IL-33 may play an important role in T cells (Tregs) following allergen exposure.150 Engagement of the allergic inflammation and immunity against parasitic infection by PD-1 receptor with its ligand PD-L1 causes the inhibition of CD4 T directly activating Th2 cells. IL-33 binds to its receptor and induces cell-mediated immune responses.151,152 Although the PD-1-PD-L1 the activation of NF-kB and MAPK.27 T1/ST2, a subunit of the IL-33 interaction has been described as a negative regulatory mechan- receptor, is preferentially expressed by Th2 cells and a subset of ism, ILC2-specific deletion of PD-L1 has a significant effect on ILC2s, and its expression is regulated by the transcription factor N. brasiliensis worm clearance, and such mice exhibit impaired

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Fig. 3 ILC2s may play an important role in initiating a Th2 response. The pulmonary epithelial cells, which are primary sentinels of the lung, sense allergens and release alarmins, such as IL-33, IL-25 and TSLP, which activate ILC2s to produce IL-4, IL-5, IL-13 and amphiregulin (Areg). In turn, IL-5 and IL-13 induce eosinophilia, mucus production and goblet cell hyperplasia. Areg produced by ILC2s plays an important role in tissue repair. Activated ILC2s will initiate an adaptive effector Th2 response by either direct antigen presentation through cognate MHCII-TCR interactions along with costimulatory molecules or by secreting Th2-inducing cytokines such as IL-4. In some cases, the IL-13 secreted by ILC2s drives the activation of inactive CD11b+ DCs. The activated CD11b+ DCs migrate into the mediastinal lymph node, where naïve CD4 T cells differentiate into effector Th2 cells upon cognate MHCII-peptide-TCR interactions

ICOS-ligand interaction have been shown to play critical roles in lung mucosal inflammation by regulating the production of Th2 cytokines.135,154 ILC2s express both ICOS and ICOS-L, and their expression can be induced by IL-2 and IL-7.132 ICOS-ICOS-L interactions among ILC2s cause ILC2 proliferation and activa- tion.155,156 The blockade of ICOS-ICOS-L interactions diminishes the production of IL-5 and IL-13 from activated ILC2s both in vivo and in vitro. Although ILC2s mainly express IL-5 and IL-13, they do express some IL-4.20,21 Thus, ILC2s may serve as early responders during nematode H. polygyrus infection by producing IL-4 to induce Th2 cell differentiation. IL-4 deficiency in ILC2s causes impaired generation of IL-4, IL-5 and IL-13-secreting CD4 T cells during H. polygyrus infection.23 Thus, crosstalk and direct interaction between ILC2s and CD4 T cells may contribute to the initiation, expansion and effector cytokine secretion of CD4 T cells as well as the maintenance of ILC2s.

MODULATION OF THE TYPE 2 IMMUNE RESPONSE Precise regulation of the magnitude and duration of an immune response is a result of balanced actions of effector and regulatory Fig. 4 Direct interactions between ILC2s and CD4 T cells. CD4 T cells mechanisms in the immune system. Control of immune responses may directly interact with ILC2s through MHCII-peptide-TCR. ILC2s to self-antigens and the prevention of exacerbated immune may also provide costimulatory signals to T cells through CD80, CD86, OX40L, and PD-L1. Additionally, it is possible that ILC2s induce responses to pathogens and/or allergens are the key controllers of naïve CD4 T cell differentiation into effector Th2 cells by secreting the immune system. Tregs play a critical role in self-tolerance and 157–159 IL-4. Reciprocally, activated CD4 T cells may promote ILC2 expansion prevent autoimmunity. The Th2 effector response may through IL-2 production also be regulated by Tregs, a potentially important mechanism for the regulation of allergic diseases.160,161 The differentiation/ effector Th2 cell generation and IL-13 secretion.153 Activated ILC2s development and suppressive functions of Tregs depend on the upregulate PD-L1, and the PD-1-PD-L1 interaction causes transcription factor Foxp3, which is also a marker for the increased expression of GATA3 and IL-13 by CD4 T cells. ICOS is identification of this suppressive T cell subset.162 IL-10-producing another costimulatory molecule. As discussed earlier, ICOS and the CD4 T cells, also called type 1 regulatory T cells (Tr1), may control

Cellular & Molecular Immunology (2019) 16:225 – 235 Orchestration between ILC2s and Th2 cells in shaping type 2 immune. . . RK Gurram and J Zhu 231

Fig. 5 Modulation of the type 2 immune response. Pulmonary epithelial cells sensing pathogen and allergen direct the development of ILC2s and Th2 cells. The IL-10 secreted by Tregs or Tr1 cells and TGF-β secreted by Tregs act at different stages of effector Th2 cell differentiation and control adaptive Th2 cell immunity. The functions of Tregs in regulating ILC2s are unknown. The release of IL-33 from epithelial cells, along + with IL-2 secretion by mast cells as well as retinoic acid secretion by CD103 DCs, creates a favorable environment for the generation of ILC210 cells. The IL-10 secreted from ILC210 cells may suppress ILC2 activation and thus control the immunopathology caused by other type 2 cytokines. The effect of ILCregs on ILC2s remains to be tested

163,164 the effector Th2 response in an IL-10-dependent manner. elicited by ILC2s via the secretion of IL-10. The ILC210 population The IL-10 secreted by Tregs and Tr1 cells as well as TGF-β secreted can be generated during the chronic stage of allergy induced by by Tregs may act at different stages of effector Th2 cell exposure to papain or IL-33, and the ILC210 population undergoes differentiation to control adaptive type 2 responses (Fig. 5). contraction upon removal of the stimulus.170 Based on in vitro Whether Tregs and Tr1 cells can directly regulate the functions of experiments, IL-33 along with IL-2 and retinoic acid induces ILC2s is not known. Although studies have shown that IL-33 is a alternative activation of ILC2s to generate ILC210. However, in proinflammatory cytokine, and DCs exposed to IL-33 promote RAG1-deficient mice, IL-33 significantly induces ILC210 cell Th2 responses, it has also been shown that IL-33-stimulated expansion, demonstrating that IL-2 produced by T cells may not 165 DCs enhance Treg differentiation by secreting IL-2. Strikingly, be required for ILC210 induction in vivo. IL-33-stimulated mast cells the IL-33 receptor ST2 is preferentially expressed by colonic Tregs, may produce IL-2 and thus possibly act as the source of IL-2 for 171 + and the IL-33 signaling in Tregs enhances their functionality ILC210 expansion. CD103 DCs are a potent source of retinoic through their accumulation and maintenance in the inflamed acid, and mice deficient in the CD103+ DC population show a 166 tissue. Thus, IL-33R expression on Tregs renders them reduction in the production of IL-10 from ILC210 cells, implying adaptable to the proinflammatory milieu. In addition, IL-9- retinoic acid production by lung-resident CD103+ DCs may activated ILC2s may induce Treg activation and proliferation and support the induction of alternatively activated ILC210. Finally, thus are involved in the resolution of chronic inflammation in an the activity of ILC2s may be negatively controlled by PD-1- arthritis model.167 mediated signaling172 and A20173 in a cell-intrinsic manner, and A recent finding indicates that a new subset of ILCs that are other non-Th2 cytokines, such as IL-1, IL-27, type 1 IFNs and IFNγ, capable of producing regulatory cytokines may control ILC- may regulate the plasticity of ILC2s and Th2 cells.115,116,174–178 mediated responses.168 This new subset of ILCs is designated ILCregs. Notably, unlike Tregs, ILCregs do not express the transcription factor Foxp3. By producing IL-10, ILCregs may CONCLUSIONS control the activation of ILC1s and ILC3s in the intestine, leading Initiation of the type 2 response takes place in the tissue sites to protection against innate inflammation. Although this work did where allergens or parasites are encountered. At the epithelial not investigate the functions of ILCregs in suppressing ILC2s barriers, skin, lung and intestinal epithelial cells are responsible for during type 2 inflammation, the suppressive effects of IL-10 and sensing the products of allergens and helminth parasites to TGF-β on ILC2s have been proposed.169 All CD4 T helper subsets, initiate type 2 immune responses in vivo by producing cytokines including Th1, Th2 and Th17 cells, are capable of producing IL-10. such as IL-33, IL-25 and TSLP. While Th2 cells, by producing IL-4, Whether there are IL-10-producing ILC1s and ILC3s that are IL-5 and IL-13, were initially believed to be the only major players immune suppressive requires further investigation. However, IL- driving the type 2 immune response, our current knowledge 170 10-producing ILC2s, termed ILC210 cells, have been discovered. indicates that the type 2 immune response is mediated by the The ILC210 population may control the type 2 immune response cooperative actions of Th2 cells and ILC2s.

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