Cellular & Molecular Immunology www.nature.com/cmi REVIEW ARTICLE Orchestration between ILC2s 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 asthma, atopic dermatitis, 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 cytokines, including interleukin-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 eosinophils, mast cells, and basophils 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 T helper cell (Th2); Group 2 innate lymphoid cell (ILC2); Allergy and asthma Cellular & Molecular Immunology (2019) 16:225–235; https://doi.org/10.1038/s41423-019-0210-8 INTRODUCTION eosinophils from bone marrow 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 goblet cell hyperplasia, mucus hypersecretion and helminth parasite immunity to allergic inflammation, wound smooth muscle hyperreactivity. healing, and metabolism.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 eosinophil 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 lymphocyte-like innate cells that play cells and alternatively activated M2 macrophages. 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 transcription factor 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 epithelium-derived cytokines, 1Molecular and Cellular Immunoregulation Section, Laboratory of Immune System 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 bacteria, and helminths. The first step in the initiation of the type 2 immune response occurs when the products of allergens 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 chemokines, 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 allergen 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 lymph node, 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 homeostasis.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