Innate Counterparts Research Articles

Plasticity of Innate Lymphoid Cells in Cancer.

Innate lymphoid cells (ILCs) are a heterogenous population of the innate immune system, enriched at mucosal surfaces and are pivotal regulators of immune homeostasis. ILCs are the innate counterpart of T cells. Like T cells, ILC subsets are highly plastic with their composition and function controlled by alterations in their microenvironment. This plasticity allows for the trans-differentiation between the subsets to rapidly respond to their immune environment. The tumor microenvironment (TME) is a heterogeneous milieu characterized by different cytokines and growth factors. Through interaction with the tumor microenvironment, ILCs can transdifferentiate into different subsets resulting in pro or anti-tumor immunity. Thus, studying ILC plasticity might result in new therapeutic approaches for cancer therapy. In this review, we summarize current findings of the functional and plastic heterogeneity of ILCs in homeostasis as well as disease settings with a specific focus on cancer. We specifically highlight tumor-driven plasticity and how ILC-induced inflammation can impact the tumor microenvironment and anti-tumor immunity.

The role of Cul5 in Group 2 innate lymphoid cells (ILC2s)

Abstract Over the past few years we have witnessed a change in the study of allergic inflammation from a view that holds T helper type 2 cells at the centre of immune orchestration to one that appreciates the significant contribution made by innate lymphoid type 2 cells (ILC2s). ILC2 cells are considered to be the innate counterpart of Th2 cells and these two evolutionarily related cells cooperate to protect the host against helminth infection and, when dysregulated, in the pathogenesis of allergic diseases. We recently determined that the E3 ubiquitin ligase Cul5 limits the differentiation and pathogenicity of Th2 cells and protects against allergic airway remodelling in mice. Here we show that Cul5 also regulates ILC2 cells. Specifically, following IL-33 treatment, mice lacking Cul5 in all hematopoietic cells contained increased numbers of ILC2 cells in their lungs and this corelated with significant Type 2 inflammation. Additionally, in the absence of Cul5, ILC2 cells were more likely to produce IL-9. Similar results were also observed in mice lacking Cul5 specifically in ILC2 cells (Cul5fl/fl-R5/+), supporting that Cul5 restricts the numbers and function of ILC2 cells. Ex vivo and following in vitro culture, Cul5-deficient ILC2 cells exhibited distinct features that would likely impact their responsiveness to environmental cues such as cytokines. Here we will detail how Cul5 impacts the differentiation and function of ILC2 cells and how this may alter the outcome of type 2 immune responses.

The Metabolic Basis of ILC Plasticity.

Innate Lymphoid Cells (ILCs) are the innate counterpart of adaptive lymphoid T cells. They are key players in the regulation of tissues homeostasis and early inflammatory host responses. ILCs are divided into three groups, and further subdivided into five subsets, that are characterised by distinct transcription factors, surface markers and their cytokine expression profiles. Group 1 ILCs, including natural killer (NK) cells and non-NK cell ILC1s, express T-bet and produce IFN-γ. Group 2 ILCs depend on GATA3 and produce IL-4, IL-5 and IL-13. Group 3 ILCs, composed of ILC3s and Lymphoid Tissue Inducer (LTi) cells, express RORγt and produce IL-17 and IL-22. Even though, the phenotype of each subset is well defined, environmental signals can trigger the interconversion of phenotypes and the plasticity of ILCs, in both mice and humans. Several extrinsic and intrinsic drivers of ILC plasticity have been described. However, the changes in cellular metabolism that underlie ILC plasticity remain largely unexplored. Given that metabolic changes critically affect fate and effector function of several immune cell types, we, here, review recent findings on ILC metabolism and discuss the implications for ILC plasticity.

Differential regulation of transcription factor T-bet induction during NK cell development and T helper-1 cell differentiation

Adaptive CD4+ T helper cells and their innate counterparts, innate lymphoid cells, utilize an identical set of transcription factors (TFs) for their differentiation and functions. However, similarities and differences in the induction of these TFs in related lymphocytes are still elusive. Here, we show that T helper-1 (Th1) cells and natural killer (NK) cells displayed distinct epigenomes at the Tbx21 locus, which encodes T-bet, a critical TF for regulating type 1 immune responses. The initial induction of T-bet in NK precursors was dependent on the NK-specific DNase I hypersensitive site Tbx21-CNS-3, and the expression of the interleukin-18 (IL-18) receptor; IL-18 induced T-bet expression through the transcription factor RUNX3, which bound to Tbx21-CNS-3. By contrast, signal transducer and activator of transcription (STAT)-binding motifs within Tbx21-CNS-12 were critical for IL-12-induced T-bet expression during Th1 cell differentiation both invitro and invivo. Thus, type 1 innate and adaptive lymphocytes utilize distinct enhancer elements for their development and differentiation.

Innate lymphoid cells in colorectal cancer.

Innate lymphoid cells (ILC) can be viewed as the innate counterparts of T cells. In contrast to T cells, ILCs exert their functions in antigen‐independent manners, relying on tissue‐derived signals from other immune cells, stroma and neurons. Natural killer (NK) cells have been known for their antitumour effects for decades. However, the roles of other ILC subtypes in cancer immunity are just now starting to be unravelled. ILCs contribute to both homeostasis and inflammation in the intestinal mucosa. Intestinal inflammation predisposes the intestine for the development of colonic dysplasia and colorectal cancer (CRC). Recent data from mouse models and human studies indicate that ILCs play a role in CRC, exerting both protumoural and antitumoural functions. Studies also suggest that intratumoural ILC frequencies and expression of ILC signature genes can predict disease progression and response to PD‐1 checkpoint therapy in CRC. In this mini‐review, we focus on such recent insights and their implications for understanding the immunobiology of CRC. We also identify knowledge gaps and research areas that require further work.

Isolation of Innate Lymphoid Cells from Murine Intestinal Lamina Propria.

Natural killer (NK) cells are innate cytotoxic immune cells essential for mediating first-line defense against various environmental antigens. With the discoveries of other subsets of innate lymphocytes over the last decade, NK cells are categorized as innate lymphoid cells (ILC) and as the innate counterparts of cytotoxic T cells. Besides NK cells, ILCs are classified into three groups distinguished by their dependence on distinct transcription factors for development and unique effector functions. Subsets of ILCs share many surface proteins that, however, have initially been identified as NK cell markers, making them hard to be distinguished for detailed investigations. Here, we describe a method to identify and individually isolate subsets of innate lymphoid cells from gut lamina propria using cell surface markers.

A mitochondrial STAT3-methionine metabolism axis promotes ILC2-driven allergic lung inflammation

Group 2 innate lymphoid cells (ILC2s), the innate counterpart of TH2 cells, play a critical role in type 2 immune responses. However, the molecular regulatory mechanisms of ILC2s are still unclear. The aim of this study was to explore the importance of signal transducer and activator of transcription 3 (STAT3) to ILC2 function in allergic lung inflammation. Acute and chronic asthma models were established by intranasal administration of the protease allergen papain in VavicreStat3fl/fl, Il5tdtomato-creStat3fl/fl, and RorccreStat3fl/fl mice to verify the necessity of functional STAT3 for ILC2 allergic response. The intrinsic role of STAT3 in regulating ILC2 function was examined by generation of bone marrow chimera mice. The underlying mechanism was studied through confocal imaging, metabolomics analysis, and chromatin immunoprecipitation quantitative PCR. STAT3 is essential for ILC2 effector function and promotes ILC2-driven allergic inflammation in the lung. Mechanistically, the alarmin cytokine IL-33 induces a noncanonical STAT3 phosphorylation at serine 727 in ILC2s, leading to translocation of STAT3 into the mitochondria. Mitochondrial STAT3 further facilitates adenosine triphosphate synthesis to fuel the methionine cycle and generation of S-adenosylmethionine, which supports the epigenetic reprogramming of type 2 cytokines in ILC2s. STAT3 deficiency, inhibition of STAT3 mitochondrial translocation, or blockade of methionine metabolism markedly dampened the ILC2 allergic response and ameliorated allergic lung inflammation. The mitochondrial STAT3-methionine metabolism pathway is a key regulator that shapes ILC2 effector function through epigenetic regulation, and the related proteins or metabolites represent potential therapeutic targets for allergic lung inflammation.

The Role of Innate Lymphoid Cells in Chronic Respiratory Diseases.

The lung is a vital mucosal organ that is constantly exposed to the external environment, and as such, its defenses are continuously under threat. The pulmonary immune system has evolved to sense and respond to these danger signals while remaining silent to innocuous aeroantigens. The origin of the defense system is the respiratory epithelium, which responds rapidly to insults by the production of an array of mediators that initiate protection by directly killing microbes, activating tissue-resident immune cells and recruiting leukocytes from the blood. At the steady-state, the lung comprises a large collection of leukocytes, amongst which are specialized cells of lymphoid origin known as innate lymphoid cells (ILCs). ILCs are divided into three major helper-like subsets, ILC1, ILC2 and ILC3, which are considered the innate counterparts of type 1, 2 and 17 T helper cells, respectively, in addition to natural killer cells and lymphoid tissue inducer cells. Although ILCs represent a small fraction of the pulmonary immune system, they play an important role in early responses to pathogens and facilitate the acquisition of adaptive immunity. However, it is now also emerging that these cells are active participants in the development of chronic lung diseases. In this mini-review, we provide an update on our current understanding of the role of ILCs and their regulation in the lung. We summarise how these cells and their mediators initiate, sustain and potentially control pulmonary inflammation, and their contribution to the respiratory diseases chronic obstructive pulmonary disease (COPD) and asthma.

Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes.

Type 2 innate lymphoid cells (ILC2) are the innate counterparts of Th2 cells and are critically involved in the maintenance of homeostasis in a variety of tissues. Instead of expressing specific antigen receptors, ILC2s respond to external stimuli such as alarmins released from damage. These cells help control the delicate balance of inflammation in adipose tissue, which is a determinant of metabolic outcome. ILC2s play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM) through their protective effects on tissue homeostasis. A variety of crosstalk takes place between resident adipose cells and ILC2s, with each interaction playing a key role in controlling this balance. ILC2 effector function is associated with increased browning of adipose tissue and an anti-inflammatory immune profile. Trafficking and maintenance of ILC2 populations are critical for tissue homeostasis. The metabolic environment and energy source significantly affect the number and function of ILC2s in addition to affecting their interactions with resident cell types. How ILC2s react to changes in the metabolic environment is a clear determinant of the severity of disease. Treating sources of metabolic instability via critical immune cells provides a clear avenue for modulation of systemic homeostasis and new treatments of T2DM.

Innate Lymphoid Cells in Intestinal Homeostasis and Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a heterogeneous state of chronic intestinal inflammation of unknown cause encompassing Crohn’s disease (CD) and ulcerative colitis (UC). IBD has been linked to genetic and environmental factors, microbiota dysbiosis, exacerbated innate and adaptive immunity and epithelial intestinal barrier dysfunction. IBD is classically associated with gut accumulation of proinflammatory Th1 and Th17 cells accompanied by insufficient Treg numbers and Tr1 immune suppression. Inflammatory T cells guide innate cells to perpetuate a constant hypersensitivity to microbial antigens, tissue injury and chronic intestinal inflammation. Recent studies of intestinal mucosal homeostasis and IBD suggest involvement of innate lymphoid cells (ILCs). These lymphoid-origin cells are innate counterparts of T cells but lack the antigen receptors expressed on B and T cells. ILCs play important roles in the first line of antimicrobial defense and contribute to organ development, tissue protection and regeneration, and mucosal homeostasis by maintaining the balance between antipathogen immunity and commensal tolerance. Intestinal homeostasis requires strict regulation of the quantity and activity of local ILC subpopulations. Recent studies demonstrated that changes to ILCs during IBD contribute to disease development. A better understanding of ILC behavior in gastrointestinal homeostasis and inflammation will provide valuable insights into new approaches to IBD treatment. This review summarizes recent research into ILCs in intestinal homeostasis and the latest advances in the understanding of the role of ILCs in IBD, with particular emphasis on the interaction between microbiota and ILC populations and functions.

B cell residency but not T cell–independent IgA switching in the gut requires innate lymphoid cells

Immunoglobulin A (IgA)-producing plasma cells derived from conventional B cells in the gut play an important role in maintaining the homeostasis of gut flora. Both T cell-dependent and T cell-independent IgA class switching occurs in the lymphoid structures in the gut, whose formation depends on lymphoid tissue inducers (LTis), a subset of innate lymphoid cells (ILCs). However, our knowledge on the functions of non-LTi helper-like ILCs, the innate counter parts of CD4 T helper cells, in promoting IgA production is still limited. By cell adoptive transfer and utilizing a unique mouse strain, we demonstrated that the generation of IgA-producing plasma cells from B cells in the gut occurred efficiently in the absence of both T cells and helper-like ILCs and without engaging TGF-β signaling. Nevertheless, B cell recruitment and/or retention in the gut required functional NKp46-CCR6+ LTis. Therefore, while CCR6+ LTis contribute to the accumulation of B cells in the gut through inducing lymphoid structure formation, helper-like ILCs are not essential for the T cell-independent generation of IgA-producing plasma cells.

The dual function of ILC2: From host protection to pathogenic players in type 2 asthma

Innate lymphoid cells type 2 (ILC2) are considered the innate counterpart of Th2 cells and cooperate with them in host protection against helminths and in the pathogenesis of allergic diseases. ILC2 are characterized by type 2 cytokines production (IL-13, IL-4 and IL-5) and by GATA-3 transcription factor expression. Belonging to innate immune system, ILC2 lack of antigen specific receptor and their activation is controlled mainly by epithelial derived cytokines, such as TSLP, IL-25, and IL-33. ILC2 are located in a strategic position in the airway mucosa and are important to patrol the airways, to recruit other immune system cells and to activate resident cells in response to pathogens injury and/or tissue damage.In the last decade, many studies, in both humans and mice, focused on ILC2, fully investigating their main features such as the development from the precursor, the stimuli for their activation or inhibition, their plasticity, their classification in different subsets, and finally, their pathogenetic role in type 2 immune-mediated disorders.In this review we performed an excursus on phenotypical and functional properties on both human and mouse ILC2, in physiological and pathological conditions (mainly in type 2 asthma), considering this cell subset as target for specific therapeutic strategies.

Differential Regulation of Transcription Factor T-Bet Induction During NK Cell Development and Th1 Cell Differentiation

Adaptive CD4 T helper cells and their innate counterparts, innate lymphoid cells, utilize an identical set of lineage-determining transcription factors (LDTFs) for their differentiation and functions. However, similarities and differences in the induction of LDTFs in these lymphocytes are still elusive. Here we show that type 1 T helper (Th1) cells and natural killer (NK) cells displayed distinct epigenomes at the Tbx21 locus, which encodes T-bet, the LDTF for type 1 lymphocytes. The initial induction of T-bet in NK precursors was dependent on the NK-specific DNase I hypersensitive site Tbx21-CNS-3 and the expression of IL-18 receptor; IL-18 induced T-bet expression through RUNX3, which bound to Tbx21-CNS-3 . By contrast, STAT-binding motifs within Tbx21-CNS-12 were critical for IL-12-induced T-bet expression during Th1 cell differentiation both in vitro and in vivo . Thus, type 1 innate and adaptive lymphocytes utilize distinct enhancer elements for their development and differentiation.

ILC3, a Central Innate Immune Component of the Gut-Brain Axis in Multiple Sclerosis.

Gut immune cells have been increasingly appreciated as important players in the central nervous system (CNS) autoimmunity in animal models of multiple sclerosis (MS). Among the gut immune cells, innate lymphoid cell type 3 (ILC3) is of special interest in MS research, as they represent the innate cell counterpart of the major pathogenic cell population in MS, i.e. T helper (Th)17 cells. Importantly, these cells have been shown to stimulate regulatory T cells (Treg) and to counteract pathogenic Th17 cells in animal models of autoimmune diseases. Besides, they are also well known for their ability to stabilize the intestinal barrier and to shape the immune response to the gut microbiota. Thus, proper maintenance of the intestinal barrier and the establishment of the regulatory milieu in the gut performed by ILC3 may prevent activation of CNS antigen-specific Th17 cells by the molecular mimicry. Recent findings on the role of ILC3 in the gut-CNS axis and their relevance for MS pathogenesis will be discussed in this paper. Possibilities of ILC3 functional modulation for the benefit of MS patients will be addressed, as well.

Biomarkers for Malignant Pleural Mesothelioma-A Novel View on Inflammation.

Simple SummaryIn view of the recent advances in immunoncology, we want to reevaluate and summarize the role of the immune system in malignant pleural mesothelioma (MPM). MPM is an aggressive disease with limited treatment options and devastating prognosis. Exposure to asbestos and chronic inflammation have long been acknowledged as main risk factors. In this review, we summarize the current knowledge about local and systemic inflammation promoting pathogenesis and progression of MPM. We focus on the prognostic and predictive value of infiltrating immune cells within the tumor and its microenvironment as local inflammation on the one hand and systemic inflammatory parameters on the other. We found that suppression of the specific and activation of the unspecific immune system are essential drivers of MPM, resulting in poor patient outcome. Numerous local and systemic inflammatory parameters are promising potential biomarkers for MPM, worth further research.Malignant pleural mesothelioma (MPM) is an aggressive disease with limited treatment response and devastating prognosis. Exposure to asbestos and chronic inflammation are acknowledged as main risk factors. Since immune therapy evolved as a promising novel treatment modality, we want to reevaluate and summarize the role of the inflammatory system in MPM. This review focuses on local tumor associated inflammation on the one hand and systemic inflammatory markers, and their impact on MPM outcome, on the other hand. Identification of new biomarkers helps to select optimal patient tailored therapy, avoid ineffective treatment with its related side effects and consequently improves patient’s outcome in this rare disease. Additionally, a better understanding of the tumor promoting and tumor suppressing inflammatory processes, influencing MPM pathogenesis and progression, might also reveal possible new targets for MPM treatment. After reviewing the currently available literature and according to our own research, it is concluded that the suppression of the specific immune system and the activation of its innate counterpart are crucial drivers of MPM aggressiveness translating to poor patient outcome.

Innate Lymphoid Cells in the Malignant Melanoma Microenvironment.

Simple SummaryInnate lymphoid cells (ILCs) are the innate counterparts of adaptive immune cells. Emerging data indicate that they are also key players in the progression of multiple tumors. In this review we briefly describe ILCs’ functions in the skin, lungs and liver. Next, we analyze the role of ILCs in primary cutaneous melanoma and in its most frequent and deadly metastases, those in liver and lung. We focus on their dual anti– and pro-tumoral functions, depending on the cross-interactions among them and with the surrounding stromal cells that form the tumor microenvironment (TME) in each organ. Next, we detail the role of extracellular vesicles secreted to the TME by ILCs and melanoma on both cell populations. We conclude that the identification of markers and tools to allow the modulation of individual ILC subsets, in addition to the development of standardized protocols, is essential for addressing the therapeutic modulation of ILCs.The role of innate lymphoid cells (ILCs) in cancer progression has been uncovered in recent years. ILCs are classified as Type 1, Type 2, and Type 3 ILCs, which are characterized by the transcription factors necessary for their development and the cytokines and chemokines they produce. ILCs are a highly heterogeneous cell population, showing both anti– and protumoral properties and capable of adapting their phenotypes and functions depending on the signals they receive from their surrounding environment. ILCs are considered the innate counterparts of the adaptive immune cells during physiological and pathological processes, including cancer, and as such, ILC subsets reflect different types of T cells. In cancer, each ILC subset plays a crucial role, not only in innate immunity but also as regulators of the tumor microenvironment. ILCs’ interplay with other immune and stromal cells in the metastatic microenvironment further dictates and influences this dichotomy, further strengthening the seed-and-soil theory and supporting the formation of more suitable and organ-specific metastatic environments. Here, we review the present knowledge on the different ILC subsets, focusing on their interplay with components of the tumor environment during the development of primary melanoma as well as on metastatic progression to organs, such as the liver or lung.

Plasticity and regulatory mechanisms of human ILC2 functions

Human group 2 innate lymphoid cells (ILC2) represent the innate counterpart of Th2 cells and cooperate with them in helminths protection and in the pathogenesis of allergic diseases. Some reports described ILC2 plasticity and few studies investigated the cellular and molecular mechanisms regulating human ILC2 functions. The aim of this study is to define how immune deviation and immune regulation control human ILC2-mediated immune response. Human circulating ILC2 were expanded in vitro and then cultured in presence of IL-12 or IL-1β plus IL-23 or co-coltured in presence of circulating CD4+CD25highFoxp3+Treg. IL-12 induces IFN-γ production and upregulation of T-bet mRNA level on human circulating ILC2 whereas IL-1β and IL-23 mediate IL-22 production and upregulation of RORC mRNA level. In all these conditions, GATA-3 mRNA level is not reduced and the typical type 2 cytokines are only partially reduced. Moreover, “modulated” ILC2 have reduced ability to induce IgE producing by B cells. ILC2 proliferation, cytokines production and CD154 expression were inhibited by CD4+CD25highFoxp3+ Treg cells. TGF-β reduced CD154 expression on ILC2 stimulated with IL-25/IL-33. This study defines possible cellular and molecular mechanisms responsible for modulation and inhibition of human ILC2 activity. These results may be useful in the development of strategies aimed to dampen ILC2 function in type-2 mediated diseases.

Differential recruitment and activation of mucosal and systemic ILC for improved vaccine design

Abstract Innate lymphoid cells (ILC) have emerging roles in immune modulation, tissue homeostasis, and inflammation. ILC may function as innate counterparts of T cells, influencing early host responses against infection or vaccination, potentially modulating development of adaptive immune responses. Little is known, however, of their recruitment and activation following immunization. Here, we investigated the activity of ILC populations after immunization with poxvirus-based vaccine vectors. Our data suggest that fowlpox virus (FPV) and modified vaccinia Ankara strain (MVA) vectors can differentially polarize ILC responses at mucosae. Intranasal (IN) delivery of FPV vectors increased numbers of pulmonary ILC1 and ILC3 subsets expressing IL-17a and IL-22 through 72 hours post-immunization. In contrast, MVA vectors given IN enhanced pulmonary ILC2 numbers and their expression of IL-13. Our previous work indicated that mucosal immunization with these vectors induced high avidity T cell responses associated with transient inhibition of IL-4/13 expression by local ILC2. Since IL-25 has been shown to down regulate IL-12 and promote ILC2/IL-13 expression, we delivered FPV encoding an IL-25 binding protein (IL-25BP) in order to sequester host IL-25 at the site of immunization. While mucosal delivery of FPV-IL-25BP appeared to induce ILC2/IL-13 expression in the lungs, IM delivery reduced ILC2/IL-13 expression, increased IL-17a expression by local ILC1 and ILC3, and enhanced Th1-type adaptive immune responses against co-expressed vaccine antigens. Together, our findings suggest that manipulation of ILC responses by vaccine vectors, co-expressed immune modulators, and delivery route may be exploited for improved vaccine design.

Quantitative Expression of GATA3 Specifies Lineage Fates and Functions of Innate Lymphoid Cells

Abstract Innate lymphoid cells (ILCs) are the innate counterparts of the CD4 T helper cells of the adaptive system. While the CD4 T cell development and differentiation have been well studied, the development of ILC subsets is far from clear. Lymphoid tissue inducer (LTi) population is the founding member of ILCs, however, recent study has shown that these cells are not derived from a PLZF-expressing ILC common progenitor that generates other ILCs. The transcription factor(s) determining the fate of non-LTi progenitor versus LTi progenitor are unknown. Here we report that GATA3 is absolutely required for the generation of PLZF-expressing non-LTi progenitors, which express high level of GATA3, but not for the generation of RORgammat-expressing LTi progenitors consistent with low levels of GATA3 expression in these progenitors. Nevertheless, low level of GATA3 expression by LTi progenitors is critical for the generation of functional LTi cells. Thus, quantitative expression of GATA3 functionally determines the fates and functions of distinct ILC progenitors.

Group 2 Innate Lymphoid Cells: Central Players in a Recurring Theme of Repair and Regeneration.

Innate lymphoid cells (ILCs) are recently discovered innate counterparts to the well-established T helper cell subsets and are most abundant at barrier surfaces, where they participate in tissue homeostasis and inflammatory responses against invading pathogens. Group 2 innate lymphoid cells (ILC2s) share cytokine and transcription factor expression profiles with type-2 helper T cells and are primarily associated with immune responses against allergens and helminth infections. Emerging data, however, suggests that ILC2s are also key regulators in other inflammatory settings; both in a beneficial context, such as the establishment of neonatal immunity, tissue repair, and homeostasis, and in the context of pathological tissue damage and disease, such as fibrosis development. This review focuses on the interactions of ILC2s with stromal cells, eosinophils, macrophages, and T regulatory cells that are common to the different settings in which type-2 immunity has been explored. We further discuss how an understanding of these interactions can reveal new avenues of therapeutic tissue regeneration, where the role of ILC2s is yet to be fully established.