Role of myeloid cells in the regulation of group 2 innate lymphoid cell-mediated allergic inflammation

Group 2 innate lymphoid cells (ILC2s) are an important component of the innate immune system that execute important effector functions at barrier surfaces, such as lung and skin. Like T helper type 2 cells, ILC2s are able to release high amounts of type 2 cytokines that are essential in inducing allergic inflammation and eliminating helminth infections. The past few years have contributed to our better understanding of the interactions between ILC2s and other cells of the immune system via soluble factors or in a cell–cell contact manner. Myeloid cells, including mononuclear leukocytes and polymorphonuclear leukocytes, are excellent sensors of tissue damage and infection and can influence ILC2 responses in the process of allergic inflammation. In this review, we summarize recent insights on how myeloid cell subsets regulate ILC2 activation with focus on soluble factors in the context of allergic inflammation.     

Ⅱ型固有淋巴细胞在白色脂肪棕色化中的作用

正Ⅱ型固有淋巴细胞(typeⅡinnate lymphoid cells,ILC2s)于2001年被发现,由共同淋巴样祖细胞发育而来,广泛分布在血液、肠道、气管、肺脏、脾脏、肝脏、动物脂肪和皮肤等部位,经白细胞介素(interleukin,IL)-25或IL-33刺激后可产生IL-5和IL-13等2型辅助性T(type 2 helper T,Th2)细胞因子,在Th2     

Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis

Group 2 innate lymphoid cells (ILC2s) have an important role in acute allergic lung inflammation. Given their distribution and function, lung ILC2s are hypothesized to coordinate epithelial responses to the external environment; however, how barrier surveillance is linked to ILC2 activation remains unclear. Here, we demonstrate that alveolar type II cells are the main source of interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) generated in response to chitin or migratory helminths. IL-33 and TSLP synergistically induce an interferon regulatory factor 4 (IRF4)-IL-9 program in ILC2s, and autocrine IL-9 promotes rapid IL-5 and IL-13 production required for optimal epithelial responses in the conducting airways. Thus, ILC2s link alveolar function to regulation of airway flow, revealing a key interaction between resident lymphoid and structural cells that might underlie similar organizational hierarchies in other organs.     

Innate and adaptive type 2 immunity in lung allergic inflammation

Allergic inflammation is a type 2 immune disorder classically characterized by high levels of immunoglobulin E (IgE) and the development of Th2 cells. Asthma is a pulmonary allergic inflammatory disease resulting in bronchial hyper-reactivity. Atopic asthma is defined by IgE antibody-mediated mast cell degranulation, while in non-atopic asthma there is no allergen-specific IgE and more involvement of innate immune cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils. Recently, protease allergens were shown to cause asthmatic responses in the absence of Th2 cells, suggesting that an innate cell network (IL-33/TSLP-basophil-ILC2-IL-5/IL-13 axis) can facilitate the sensitization phase of type 2 inflammatory responses. Recent evidence also indicates that in the chronic phase, these innate immune cells directly or indirectly contribute to the adaptive Th2 cell responses. In this review, we discuss the role of Th2 cytokines (IL-4 and IL-13) and innate immune cells (mast cells, basophils, ILC2s, and dendritic cells) in the cross-talk between innate and adaptive inflammatory responses.     

The prostaglandin D2 receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung

Group 2 innate lymphoid cells (ILC2s) promote type 2 cytokine-dependent immunity, inflammation, and tissue repair. Although epithelial cell-derived cytokines regulate ILC2 effector functions, the pathways that control the in vivo migration of ILC2s into inflamed tissues remain poorly understood. Here, we provide the first demonstration that expression of the prostaglandin D₂ (PGD₂) receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) regulates the in vivo accumulation of ILC2s in the lung. Although a significant proportion of ILC2s isolated from healthy human peripheral blood expressed CRTH2, a smaller proportion of ILC2s isolated from nondiseased human lung expressed CRTH2, suggesting that dynamic regulation of CRTH2 expression might be associated with the migration of ILC2s into tissues. Consistent with this, murine ILC2s expressed CRTH2, migrated toward PGD₂in vitro, and accumulated in the lung in response to PGD₂in vivo. Furthermore, mice deficient in CRTH2 exhibited reduced ILC2 responses and inflammation in a murine model of helminth-induced pulmonary type 2 inflammation. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored pulmonary inflammation in CRTH2-deficient mice. Together, these data identify a role for the PGD₂–CRTH2 pathway in regulating the in vivo accumulation of ILC2s and the development of type 2 inflammation in the lung.     

Necroptotic cell death in anti-cancer therapy

Asthma is a complex heterogeneous disease of the airways characterized by lung inflammation, airway hyperreactivity (AHR), mucus overproduction, and remodeling of the airways. Group 2 innate lymphoid cells (ILC2s) play a crucial role in the initiation and propagation of type 2 inflammatory programs in allergic asthma models, independent of adaptive immunity. In response to allergen, helminths or viral infection, damaged airway epithelial cells secrete IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), which activate ILC2s to produce type 2 cytokines such as IL-5, IL-13, and IL-9. Furthermore, ILC2s coordinate a network of cellular responses and interact with numerous cell types to propagate the inflammatory response and repair lung damage. ILC2s display functional plasticity in distinct asthma phenotypes, enabling them to respond to very different immune microenvironments. Thus, in the context of non-allergic asthma, triggered by exposure to environmental factors, ILC2s transdifferentiate to ILC1-like cells and activate type 1 inflammatory programs in the lung. In this review, we summarize accumulating evidence on the heterogeneity, plasticity, regulatory mechanisms, and pleiotropic roles of ILC2s in allergic inflammation as well as mechanisms for their suppression in the airways.     

IL-27 suppresses type 2 immune responses in vivo via direct effects on group 2 innate lymphoid cells

Group 2 innate lymphoid cells (ILC2) were recently characterized by their ability to produce significant amounts of type-2 signature cytokines and drive central beneficial and pathological features of type-2 immune responses. Although factors such as IL-33 and IL-25 were shown to have ILC2 activating capacity, it is not well understood, how ILC2 responses are regulated in vivo. Here we provide compelling evidence that IL-27-signalling directly inhibits ILC2 responses and reveal a novel mechanism for negative regulation of the innate arm of type-2 immunity. We demonstrate that IL-27-deficiency is linked to increased mucosal presence of ILC2 in a model of inflammatory lung disease. Moreover, IL-27-treatment inhibited ILC2 proliferation and cytokine production and significantly reduced their accumulation in vivo. During helminth infection, regulation of ILC2 by IL-27 directly impacted anti-parasitic immunity. Thus, therapeutic modulation of the IL-27/IL-27R axis may be relevant in a number of inflammatory conditions associated with dysregulated type-2 responses.     

TNF superfamily member TL1A elicits type 2 innate lymphoid cells at mucosal barriers

Immune responses at mucosal barriers are regulated by innate type 2 lymphoid cells (ILC2s) that elaborate effector cytokines interleukins 5 and 13 (IL5 and IL13). IL25 and IL33 are key cytokines that support ILC2s; however, mice deficient in these pathways retain some functional ILC2s. Analysis of human and murine cells revealed that ILC2s highly express tumor necrosis factor (TNF)-receptor superfamily member DR3 (TNFRSF25). Engagement of DR3 with cognate ligand TL1A promoted ILC2 expansion, survival, and function. Exogenous protein or genetic overexpression of TL1A activated ILC2s independent of IL25 or IL33. Dr3^−/− mice failed to control gut helminthic infections, and failed to mount ILC2 responses in the lung after nasal challenge with papain. Our data demonstrate a key role for TL1A in promoting ILC2s at mucosal barriers.     

ICOS protects against mortality from acute lung injury through activation of IL-5+ ILC2s

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreversible lung scarring and loss of pulmonary function. IPF Patients suffer from a high rate of pulmonary infections and acute exacerbations of disease that further contribute to pulmonary decline. Low expression of the inducible T-cell costimulatory molecule (ICOS) in peripheral blood mononuclear cells predicts decreased survival of IPF patients, but the mechanisms by which ICOS protects are unclear. Using a model of bleomycin-induced lung injury and fibrosis, we now demonstrate that ICOS expression enhances survival from lung injury rather than regulating fibrogenesis. Of ICOS-expressing cells, type 2 innate lymphocytes (ILC2s) are the first to respond to bleomycin-induced injury, and this expansion is ICOS dependent. Interestingly, a similar decrease in ICOS⁺ ILCs was found in lung tissue from IPF patients. Interleukin (IL)-5, produced primarily by ILC2s, was significantly reduced after lung injury in ICOS^−/− mice, and strikingly, treatment with IL-5 protected both ICOS^−/− and wild-type mice from mortality. These results imply that low ICOS expression and decreased lung ILC2s in IPF patients may contribute to poor recovery from infections and acute exacerbation and that IL-5 treatment may be a novel therapeutic strategy to overcome these defects and protect against lung injury.     

IL-33: biological properties,functions, and roles in airway disease

Interleukin (IL)-33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL-33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL-33 and group 2 innate lymphoid cells (ILC2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL-33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL-33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL-33 and ILC2 levels are elevated in patients with allergic airway diseases suggest that IL-33 plays an important role in the pathogenesis of these diseases. IL-33 and ILC2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL-33 and discussed the roles of the IL-33 in regulating airway immune responses and allergic airway diseases.     

Regulatory T cells and type 2 innate lymphoid cell‐dependent asthma

Group 2 innate lymphoid cells (ILC2s) are a recently identified group of cells with the potent capability to produce Th2‐type cytokines such as interleukin (IL)‐5 and IL‐13. Several studies suggest that ILC2s play an important role in the development of allergic diseases and asthma. Activation of pulmonary ILC2s in murine models lacking T and B cells induces eosinophilia and airway hyper‐reactivity (AHR), which are cardinal features of asthma. More importantly, numerous recent studies have highlighted the role of ILC2s in asthma persistence and exacerbation among human subjects, and thus, regulation of pulmonary ILC2s is a major area of investigation aimed at curbing allergic lung inflammation and exacerbation. Emerging evidence reveals that a group of regulatory T cells, induced Tregs (iTregs), effectively suppress the production of ILC2‐driven, pro‐inflammatory cytokines IL‐5 and IL‐13. The inhibitory effects of iTregs are blocked by preventing direct cellular contact or by inhibiting the ICOS‐ICOS‐ligand (ICOSL) pathway, suggesting that both direct contact and ICOS‐ICOSL interaction are important in the regulation of ILC2 function. Also, cytokines such as IL‐10 and TGF‐β1 significantly reduce cytokine secretion by ILC2s. Altogether, these new findings uncover iTregs as potent regulators of ILC2 activation and implicate their utility as a therapeutic approach for the treatment of ILC2‐mediated allergic asthma and respiratory disease.     

ILC2 memory: Recollection of previous activation

Immunological memory, traditionally thought to belong to T and B cells, has now been extended to innate lymphocytes, including NK cells and ILC2s, myeloid cells such as macrophages, also termed “trained immunity” and more recently to epithelial stem cells. In this review, we discuss the mechanisms underlying memory generation on ILC2s and speculate about their potential role in human allergic diseases, such as asthma. Moreover, we examine the relevance of the spontaneous ILC2 activation in the lung during the neonatal period in order to efficiently respond to stimuli later in life. These “training” of neonatal ILC2s may have an impact on the generation of memory ILC2s in the adulthood.     

Type 2 innate lymphoid cells: at the cross-roads in allergic asthma

Allergic asthma is a chronic inflammatory disease of the lower airways that affects millions of people worldwide. Allergic asthma is a T helper 2 cell (Th2)-mediated disease, in which Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 are closely associated with the symptoms. IL-4 is needed by B cells to switch toward an IgE response, IL-5 recruits and activates eosinophils while IL-13 increases mucus production. The identification of type 2 innate lymphoid cells (ILC2), which are able to rapidly produce large amounts of IL-5 and IL-13 in response to epithelial derived cytokines, implicated a new key player besides Th2 cells. ILCs constitute a family of innate lymphocytes distinct from T and B cells. ILC2s are located in various epithelial compartments in mice and human, including the lung. The recent finding of increased numbers of ILC2s in the airways of severe asthma patients prompts further research to clarify their immunological function. Murine studies have shown that ILC2s are an early innate source of IL-5 and IL-13 after allergen exposure, which induce airway eosinophilic infiltration, mucus hyperproduction, and airway hyperresponsiveness but not allergen-specific IgE production. ILC2s contribute to the initiation as well as to the maintenance of the adaptive type 2 immune response. Here, we review the recent progress on our understanding of the role of ILC2s in the immunopathology of allergic asthma, in particular by studies using murine models which have elucidated fundamental mechanisms by which ILC2s act.     

ICOS regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice

Group 2 innate lymphoid cells (ILC2s) are innate effectors playing an important role in the defense against helminthic infections and in the pathogenesis of allergic inflammation. Cytokines have been identified as the major stimuli driving ILC2 activation and expansion. Conversely, it is unclear whether costimulatory molecules contribute to regulation of ILC2 functions. ILC2s display high expression of inducible T‐cell costimulator (ICOS), which belongs to the CD28 superfamily, and which has been shown to control late effector T‐cell functions, and is of utmost importance for the humoral immune response. However, the biological function of ICOS expression on ILC2s is unknown. Here, we show that ICOS signaling in mice regulates ILC2 homeostasis independently of T cells and B cells, by promoting proliferation and accumulation of mature ILC2s in lung and intestine. In a model of IL‐33‐induced airway inflammation, ICOS controls ILC2 activation and eosinophil infiltration in the lung. Our data identify a role of ICOS in innate immunity and indicate that not only cytokines, but also costimulatory pathways such as those involving ICOS, can contribute to regulate the ILC2 pool. Thus, ICOS costimulation blockade, which is currently under clinical evaluation for inhibiting the humoral immune response, could also target innate inflammatory circuits.     

Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma

Allergic asthma is characterized by chronic airway inflammation and hyperreactivity and is thought to be mediated by an adaptive T helper-2 (Th2) cell-type immune response. Here, we demonstrate that type 2 pulmonary innate lymphoid cells (ILC2s) significantly contribute to production of the key cytokines IL-5 and IL-13 in experimental asthma. In naive mice, lineage-marker negative ILC2s expressing IL-7Rα, CD25, Sca-1, and T1/ST2(IL-33R) were present in lungs and mediastinal lymph nodes (MedLNs), but not in broncho-alveolar lavage (BAL) fluid. Upon intranasal administration of IL-25 or IL-33, an asthma phenotype was induced, whereby ILC2s accumulated in lungs, MedLNs, and BAL fluid. After IL-25 and IL-33 administration, ILC2s constituted ～50 and ～80% of IL-5(+) /IL-13(+) cells in lung and BAL, respectively. Also in house dust mite-induced or ovalbumin-induced allergic asthma, the ILC2 population in lung and BAL fluid increased significantly in size and ILC2s were a major source of IL-5 or IL-13. Particularly in OVA-induced asthma, the contribution of ILC2s to the total population of intracellular IL-5(+) and IL-13(+) cells in the lung was in the same range as found for Th2 cells. We conclude that both ILC2s and Th2 cells produce large amounts of IL-5 and IL-13 that contribute to allergic airway inflammation.     

第2组先天性淋巴细胞在变应性鼻炎先天性和适应性免疫应答中的作用

变应性鼻炎(AR)是特异性个体在环境过敏原暴露后出现鼻塞、清涕、喷嚏、鼻痒的变态反应性疾病.第2组先天性淋巴细胞(ILC2s)是先天性免疫家族新成员,通过与免疫细胞相互作参与先天性和适应性免疫反应诱导多种变应性疾病.ILC2s数量与AR的严重程度相关,可通过多种效应途径促进Th2细胞因子及IgE在鼻黏膜大量分泌介导鼻部...     

Spatial and temporal coordination of antiviral responses by group 1 ILCs

Group 1 innate lymphocytes consist of a phenotypically, spatially, and functionally heterogeneous population of NK cells and ILC1s that are engaged during pathogen invasion. We are only beginning to understand the context-dependent roles that different subsets of group 1 innate lymphocytes play during homeostatic perturbations. With a focus on viral infection, this review highlights the organization and regulation of spatially and temporally distinct waves of NK cell and ILC1 responses that collectively serve to achieve optimal viral control.     

Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation

Thymic stromal lymphopoietin (TSLP) is a critical upstream cytokine inducing type 2 inflammation in various diseases, including asthma and atopic dermatitis. Accumulating evidence suggests that TSLP can directly stimulate a variety of immune cells, such as dendritic cells (DCs), basophils, T cells, and group 2 innate lymphoid cells (ILC2s). However, which cell types directly respond to TSLP in vivo and how TSLP initiates type 2 inflammation has remained controversial. To define the precise role of TSLP in vivo, for the first time we generated multiple cell lineage-specific TSLP receptor-deficient mice to systematically dissect the cell-intrinsic requirements for TSLP responsiveness in type 2 inflammation in the lung. In papain-induced innate immune-mediated type 2 airway inflammation, TSLP directly stimulated ILC2s, but not basophils, leading to enhanced type 2 inflammation. On the other hand, in OVA-induced adaptive immune-mediated type 2 airway inflammation, TSLP principally acted on DCs and CD4 + T cells during the sensitization phase, but not basophils or ILC2s, and facilitated the development of Th2 cell-mediated airway inflammation. Together, these findings reveal that TSLP activates distinct immune cell cascades in the context of innate and adaptive immune-mediated type 2 inflammation.     

OASL1-Mediated Inhibition of Type I IFN Reduces Influenza A Infection-Induced Airway Inflammation by Regulating ILC2s

PurposeThree observations drove this study. First, 2′-5′-oligoadenylate synthetase-like protein (OASL) is a negative regulator of type I interferon (IFN). Second, type I IFN plays a central role during virus infections and the pathogenesis of various diseases, including asthma. Third, influenza A virus (IAV) causes non-eosinophilic asthma. To evaluate the potential relationships between OASL, type I IFN, and pulmonary innate immune cells in IAV-induced acute airway inflammation by using Oasl1^-/- mice.MethodsAsthma was induced in wild-type (WT) and Oasl1^-/- mice with IAV or ovalbumin (OVA). Airway hyperreactivity (AHR) and immune cell infiltration in the bronchoalveolar lavage (BAL) fluids were measured. The immune cells in the lungs were analyzed by flow cytometry. To investigate the ability of type I IFN to shape the response of lung type 2 innate lymphoid cells (ILC2s), IFN-α was treated intratracheally. Plasmacytoid dendritic cells (pDCs) sorted from bone marrow and ILC2s sorted from lungs of naive mice were co-cultured with/without interferon-alpha receptor subunit 1 (IFNAR-1)-blocking antibodies.ResultsIn the IAV-induced asthma model, Oasl1^-/- mice developed greater AHR and immune cell infiltration in the BAL fluids than WT mice. This was not observed in OVA-induced asthma, a standard model of allergen-induced asthma. The lungs of infected Oasl1^-/- mice also had elevated DC numbers and Ifna expression and depressed IAV-induced ILC2 responses, namely, proliferation and type 2 cytokine and amphiregulin production. Intratracheal administration of type I IFN in naïve mice suppressed lung ILC2 production of type 2 cytokines and amphiregulin. Co-culture of ILC2s with pDCs showed that pDCs inhibit the function of ILC2s by secreting type I IFN.ConclusionsOASL1 may impede the IAV-induced acute airway inflammation that drives AHR by inhibiting IAV-induced type I IFN production from lung DCs, thereby preserving the functions of lung ILC2s, including their amphiregulin production.