Cells acting at the intersection of immunityFor years, scientists divided the immune system into two arms: innate and adaptive. The cell types involved in the two arms differ in specificity and in ...how quickly they respond to infections. More recently, immunologists discovered a family of immune cells termed "innate lymphoid cells," which straddle these two arms. Eberl et al. review current understanding of innate lymphoid cells. Like innate immune cells, they respond to infection quickly and do not express antigen receptors; however, they secrete a similar suite of inflammatory mediators as T lymphocytes. Better understanding of the processes regulating these cells may allow for their therapeutic manipulation.Science, this issue 10.1126/science.aaa6566 Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.
Interleukin‐33 (IL‐33) is an IL‐1 family cytokine that signals via its receptor T1/ST2, and is a key regulator of inflammation, notably the type‐2 response implicated in allergic asthma. Critical to ...our understanding of the role of IL‐33 is the identification of the cellular sources of IL‐33. Although progress has been made in this area, the development of a robust live cell reporter of expression would allow the localisation of IL‐33 during ongoing immune responses. We have generated a fluorescent reporter mouse line, Il33Cit/+, to define the expression profile of IL‐33 in vivo and demonstrate its temporal and spatial expression during experimental allergic asthma responses. We found that type‐2 pneumocytes constitute the major source of IL‐33 upon allergic lung inflammation following exposure to OVA, fungal extract or ragweed pollen. Using Il33Cit/Cit mice (IL‐33‐deficient), we establish a role for IL‐33 early in the initiation of type‐2 responses and the induction of nuocytes (ILC2). We also demonstrate a potential mechanism of action by which IL‐33 rapidly initiates type‐2 immune responses. Il33Cit/+ mice have enabled new insights into the initiation of type‐2 responses and will provide an important tool for further dissection of this important inflammatory pathway in vivo.
Naive CD4+ T cell differentiation into distinct subsets of T helper (Th) cells is a pivotal process in the initiation of the adaptive immune response. Allergens predominantly stimulate Th2 cells, ...causing allergic inflammation. However, why allergens induce Th2 cell differentiation is not well understood. Here we show that group 2 innate lymphoid cells (ILC2s) are required to mount a robust Th2 cell response to the protease-allergen papain. Intranasal administration of papain stimulated ILC2s and Th2 cells, causing allergic lung inflammation and elevated immunoglobulin E titers. This process was severely impaired in ILC2-deficient mice. Whereas interleukin-4 (IL-4) was dispensable for papain-induced Th2 cell differentiation, ILC2-derived IL-13 was critical as it promoted migration of activated lung dendritic cells into the draining lymph node where they primed naive T cells to differentiate into Th2 cells. Papain-induced ILC2 activation and Th2 cell differentiation was IL-33-dependent, suggesting a common pathway in the initiation of Th2 cell responses to allergen.
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•ILC2-deficient mice have impaired Th2 cell responses to allergen•Allergen-induced Th2 cell differentiation is dependent on ILC2-derived IL-13•ILC2 activation by allergen requires IL-33 from epithelial cells•ILC2-derived IL-13 promotes DC migration to lymph node
Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed ...due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix components, ultimately leading to fibrosis and liver failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33’s profibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.
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•IL-33 expression is upregulated in human and murine hepatic fibrosis•IL-33 release due to hepatocellular stress induces severe hepatic fibrosis in vivo•IL-33 expands liver resident innate lymphoid cells•IL-13 from ILC2 drives liver tissue remodeling by hepatic stellate cell activation
Innate lymphoid cells (ILCs) were first described as playing important roles in the development of lymphoid tissues and more recently in the initiation of inflammation at barrier surfaces in response ...to infection or tissue damage. It has now become apparent that ILCs play more complex roles throughout the duration of immune responses, participating in the transition from innate to adaptive immunity and contributing to chronic inflammation. The proximity of ILCs to epithelial surfaces and their constitutive strategic positioning in other tissues throughout the body ensures that, in spite of their rarity, ILCs are able to regulate immune homeostasis effectively. Dysregulation of ILC function might result in chronic pathologies such as allergies, autoimmunity, and inflammation. A new role for ILCs in the maintenance of metabolic homeostasis has started to emerge, underlining their importance in fundamental physiological processes beyond infection and immunity.
Innate lymphoid cells (ILCs) can respond rapidly to changes in the tissue microenvironment with immunoregulatory cytokine production. McKenzie and colleagues review the role of ILCs in inflammation and immunity and highlight the essential role these cells play in maintaining immune homeostasis.
Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ...ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.
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•Genetic ablation of ILC2s impairs type-2 immunity•MHCII-expressing ILC2s potentiate Th2 responses•IL-2 from T cells promotes ILC2 proliferation and expression of type-2 cytokines•MHCII and IL-13 expression by ILC2s is important for N. brasiliensis expulsion
Type-2 innate lymphoid cells proliferate and release interleukin-13 during protective immunity to helminth infection and detrimentally during allergy and asthma. McKenzie and colleagues establish that these activities are potentiated through an MHC class II-mediated dialogue with T cells.
House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease ...allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient KitW-sh/W-sh mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells.
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•MC-deficient mice exhibit exacerbated papain-induced lung inflammation•Such lung inflammation is associated with reduced numbers of Treg cells•IL-2 produced by IL-33-stimulated mast cells promotes Treg cell expansion•MCs suppress papain-induced airway inflammation by numbers of Treg cells
The role of mast cells (MCs) in non-Th2 cell- and non-IgE-mediated allergic disorders is unknown. Nakae and colleagues show that IL-33-stimulated MC-derived IL-2 enhances expansion of numbers of regulatory T cells, thereby suppressing of allergic inflammation.
Background IL-25 and IL-33 belong to distinct cytokine families, but experimental mouse studies suggest their immunologic functions in type 2 immunity are almost entirely overlapping. However, only ...polymorphisms in the IL-33 pathway ( IL1RL1 and IL33 ) have been significantly associated with asthma in large-cohort genome-wide association studies. Objective We sought to identify distinct pathways for IL-25 and IL-33 in the lung that might provide insight into their roles in asthma pathogenesis and potential for therapeutic intervention. Methods IL-25 receptor–deficient (Il17rb −/− ) , IL-33 receptor–deficient (ST2, Il1rl1−/− ), and double-deficient (Il17rb −/− Il1rl1 −/− ) mice were analyzed in models of allergic asthma. Microarrays, an ex vivo lung slice airway contraction model, and Il13+/eGFP mice were then used to identify specific effects of IL-25 and IL-33 administration. Results Comparison of IL-25 and IL-33 pathway–deficient mice demonstrates that IL-33 signaling plays a more important in vivo role in airways hyperreactivity than IL-25. Furthermore, methacholine-induced airway contraction ex vivo increases after treatment with IL-33 but not IL-25. This is dependent on expression of the IL-33 receptor and type 2 cytokines. Confocal studies with Il13+/eGFP mice show that IL-33 more potently induces expansion of IL-13–producing type 2 innate lymphoid cells, correlating with airway contraction. This predominance of IL-33 activity is enforced in vivo because IL-33 is more rapidly expressed and released in comparison with IL-25. Conclusion Our data demonstrate that IL-33 plays a critical role in the rapid induction of airway contraction by stimulating the prompt expansion of IL-13–producing type 2 innate lymphoid cells, whereas IL-25–induced responses are slower and less potent.
Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. ...Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell—mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.
Background IL-4, IL-5, and IL-13 are thought to be central to the allergic asthmatic response. Previous work supposed that the essential source of these cytokines was CD4+ TH 2 cells. However, more ...recent studies have suggested that other innate production of type 2 cytokines might be as important. Objectives Nuocytes are a novel population of IL-13–producing innate cells, which are critical for protective immunity in Nippostrongylus brasiliensis infection. Given this, we investigated the potential existence and functional importance of nuocytes in experimental allergic asthma. Methods We generated Il4+/eGFP Il13+/Tomato dual-reporter mice to study cytokine-producing cells during allergic inflammation. We adoptively transferred innate IL-13–producing cells to investigate their role in airways hyperreactivity (AHR). Results We show that allergen-induced nuocytes infiltrate the lung and are a major innate source of IL-13. CD4+ T cells in the lung almost exclusively express only IL-13, whereas IL-4–producing T cells were restricted to the draining lymph nodes. Intranasal administration of IL-25 or IL-33 induced IL-13–producing nuocytes in the BAL fluid. Strikingly, adoptive transfer of wild-type nuocytes, but not Il13−/− nuocytes, into Il13−/− mice, which are normally resistant to IL-25–induced AHR, restored airways resistance and lung cell infiltration. Conclusions These findings identify nuocytes as a novel cell type in allergic lung inflammation and an innate source of IL-13 that can directly induce AHR in the absence of IL-13–producing CD4+ T cells. These data highlight nuocytes as an important new consideration in the development of future allergic asthma therapy.
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