Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells
TL;DR: It is found that deficiency in signaling via type I interferon receptor led to deregulated activation of group 2 innate lymphoid cells (ILC2 cells) and infection-associated type 2 immunopathology.
Abstract: Viral respiratory tract infections are the main causative agents of the onset of infection-induced asthma and asthma exacerbations that remain mechanistically unexplained. Here we found that deficiency in signaling via type I interferon receptor led to deregulated activation of group 2 innate lymphoid cells (ILC2 cells) and infection-associated type 2 immunopathology. Type I interferons directly and negatively regulated mouse and human ILC2 cells in a manner dependent on the transcriptional activator ISGF3 that led to altered cytokine production, cell proliferation and increased cell death. In addition, interferon-γ (IFN-γ) and interleukin 27 (IL-27) altered ILC2 function dependent on the transcription factor STAT1. These results demonstrate that type I and type II interferons, together with IL-27, regulate ILC2 cells to restrict type 2 immunopathology.
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Aix-Marseille University1, Cornell University2, Washington University in St. Louis3, Charité4, Pasteur Institute5, French Institute of Health and Medical Research6, Keio University7, University of California, San Francisco8, Laboratory of Molecular Biology9, VU University Amsterdam10, University of Oxford11, University of Amsterdam12
TL;DR: The advances in ILC biology over the past decade are distill the advances to refine the nomenclature of ILCs and highlight the importance of I LCs in tissue homeostasis, morphogenesis, metabolism, repair, and regeneration.
1,252 citations
Cites background from "Type I interferon restricts type 2 ..."
...STAT1 signals downstream of type I and type II interferons and of IL-27 are critical for suppressing ILC2 functions (Duerr et al., 2016; Molofsky et al., 2015; Moro et al., 2016), whereas STAT5 signals downstream of IL-2, IL-9, and TSLP enhance activation of ILC2, leading to steroid resistance (Kabata et al....
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TL;DR: This Review highlights experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease.
Abstract: Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease.
729 citations
TL;DR: Evidence is presented that both antiviral and immunomodulatory functions are critical during virus infection to not only limit virus replication and initiate an appropriate antiviral immune response, but to also negatively regulate this response to minimize tissue damage.
Abstract: Type I and type II interferons (IFN) are central to both combating virus infection and modulating the antiviral immune response Indeed, an absence of either the receptor for type I IFNs or IFN-y have resulted in increased susceptibility to virus infection, including increased virus replication and reduced survival However, an emerging area of research has shown that there is a dual nature to these cytokines Recent evidence has demonstrated that both type I and type II IFNs have immunoregulatory functions during infection and type II immune responses In this review, we address the dual nature of type I and type II interferons and present evidence that both antiviral and immunomodulatory functions are critical during virus infection to not only limit virus replication and initiate an appropriate antiviral immune response, but to also negatively regulate this response to minimize tissue damage Both the activating and negatively regulatory properties of type I and II IFNs work in concert with each other to create a balanced immune response that combats the infection while minimizing collateral damage
405 citations
Cites background or methods from "Type I interferon restricts type 2 ..."
...demonstrated that, similar to type I IFN, IFN-γ is able to suppress ILC2 proliferation and type 2 cytokine production (62, 89)....
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...– Reduces expression of IL-5, IL-6, and IL-13 (62)...
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...Inflammatory monocytes Recruitment: – Induction of CCL2 for inflammatory monocyte recruitment (2, 34, 36, 37) Differentiation: – Absence of IFNAR leads to decreased Ly6Chi inflammatory monocyte differentiation and results in increased levels of Ly6Cintermediate monocytes (36) Function: – Downregulation of IFNγR expression and subsequently NOS2 expression (36) Macrophages Function: – Upregulation of IL-10 and PD-L1 (50, 51) Function: – Downregulation of IFNγR expression (52) Neutrophils No evidence of activation Recruitment: – Suppresses CXCL1 and CXCL2 production (35, 38, 63) NK cells Recruitment: – Induction of CCL3, CCL4, CCL5 for NK cell recruitment (35) Activation: – Implicated in STAT-1-mediated cytotoxicity (39) – Required for IFN-γ production (2, 40–43) Suppression of IFN-γ due to: – Chronic type I IFN (48, 57, 58) – Increased levels of type I IFN (60) – Timing of type I IFN—early release results in activation, late results in inhibition (59) ILC2 No evidence of activation Proliferation: – Reduces ILC2 proliferation (62) Function: – Reduces expression of IL-5, IL-6, and IL-13 (62) Frontiers in Immunology | www.frontiersin.org 4 September 2018 | Volume 9 | Article 2061 induce NO production, a potent inhibitor of virus replication, from surrounding cells (72, 76)....
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...– Reduced expression of IL-5, IL-6, and IL-13 (62, 89)...
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...demonstrated that this pathology was mediated by an upregulation of type 2 cytokines from unregulated innate lymphoid type 2 cells (ILC2s) (62)....
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TL;DR: An updated view on the function and plasticity of human ILCs in tissue homeostasis and disease is provided.
Abstract: Innate lymphoid cells (ILCs) are increasingly acknowledged as important mediators of immune homeostasis and pathology. ILCs act as early orchestrators of immunity, responding to epithelium-derived signals by expressing an array of cytokines and cell-surface receptors, which shape subsequent immune responses. As such, ILCs make up interesting therapeutic targets for several diseases. In patients with allergy and asthma, group 2 innate lymphoid cells produce high amounts of IL-5 and IL-13, thereby contributing to type 2–mediated inflammation. Group 3 innate lymphoid cells are implicated in intestinal homeostasis and psoriasis pathology through abundant IL-22 production, whereas group 1 innate lymphoid cells are accumulated in chronic inflammation of the gut (inflammatory bowel disease) and lung (chronic obstructive pulmonary disease), where they contribute to IFN-γ–mediated inflammation. Although the ontogeny of mouse ILCs is slowly unraveling, the development of human ILCs is far from understood. In addition, the growing complexity of the human ILC family in terms of previously unrecognized functional heterogeneity and plasticity has generated confusion within the field. Here we provide an updated view on the function and plasticity of human ILCs in tissue homeostasis and disease.
329 citations
TL;DR: Functional plasticity of ILC2 cells exacerbates anti-viral immunity, which may have adverse consequences in respiratory diseases such as COPD.
Abstract: Innate lymphoid cells (ILCs) are critical mediators of mucosal immunity, and group 1 ILCs (ILC1 cells) and group 3 ILCs (ILC3 cells) have been shown to be functionally plastic. Here we found that group 2 ILCs (ILC2 cells) also exhibited phenotypic plasticity in response to infectious or noxious agents, characterized by substantially lower expression of the transcription factor GATA-3 and a concomitant switch to being ILC1 cells that produced interferon-γ (IFN-γ). Interleukin 12 (IL-12) and IL-18 regulated this conversion, and during viral infection, ILC2 cells clustered within inflamed areas and acquired an ILC1-like phenotype. Mechanistically, these ILC1 cells augmented virus-induced inflammation in a manner dependent on the transcription factor T-bet. Notably, IL-12 converted human ILC2 cells into ILC1 cells, and the frequency of ILC1 cells in patients with chronic obstructive pulmonary disease (COPD) correlated with disease severity and susceptibility to exacerbations. Thus, functional plasticity of ILC2 cells exacerbates anti-viral immunity, which may have adverse consequences in respiratory diseases such as COPD.
327 citations
References
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St. Jude Children's Research Hospital1, University of Edinburgh2, Singapore Immunology Network3, New York University4, University College London5, Heidelberg University6, University of Oxford7, Royal Melbourne Hospital8, Hospital for Special Surgery9, University of Milan10, Aix-Marseille University11, University of Maryland, College Park12, European Institute of Oncology13, Massachusetts Institute of Technology14, University of Bonn15, University of Maryland, Baltimore16, University of Eastern Piedmont17, University of Louisville18, Vrije Universiteit Brussel19, National Institutes of Health20
TL;DR: A set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation are described with the goal of unifying experimental standards for diverse experimental scenarios.
4,287 citations
University of Amsterdam1, University of Pennsylvania2, Washington University in St. Louis3, University of Freiburg4, Pasteur Institute5, University of California, San Francisco6, Laboratory of Molecular Biology7, VU University Amsterdam8, John Radcliffe Hospital9, Centre national de la recherche scientifique10, French Institute of Health and Medical Research11
TL;DR: It is proposed that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.
Abstract: Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.
2,039 citations
TL;DR: Data suggest that the use of antiviral drugs was beneficial in hospitalized patients, especially when such therapy was initiated early, and patients seemed to benefit from antiviral therapy.
Abstract: BACKGROUND During the spring of 2009, a pandemic influenza A (H1N1) virus emerged and spread globally. We describe the clinical characteristics of patients who were hospitalized with 2009 H1N1 influenza in the United States from April 2009 to mid-June 2009. METHODS Using medical charts, we collected data on 272 patients who were hospitalized for at least 24 hours for influenza-like illness and who tested positive for the 2009 H1N1 virus with the use of a real-time reverse-transcriptase-polymerase-chain-reaction assay. RESULTS Of the 272 patients we studied, 25% were admitted to an intensive care unit and 7% died. Forty-five percent of the patients were children under the age of 18 years, and 5% were 65 years of age or older. Seventy-three percent of the patients had at least one underlying medical condition; these conditions included asthma; diabetes; heart, lung, and neurologic diseases; and pregnancy. Of the 249 patients who underwent chest radiography on admission, 100 (40%) had findings consistent with pneumonia. Of the 268 patients for whom data were available regarding the use of antiviral drugs, such therapy was initiated in 200 patients (75%) at a median of 3 days after the onset of illness. Data suggest that the use of antiviral drugs was beneficial in hospitalized patients, especially when such therapy was initiated early. CONCLUSIONS During the evaluation period, 2009 H1N1 influenza caused severe illness requiring hospitalization, including pneumonia and death. Nearly three quarters of the patients had one or more underlying medical conditions. Few severe illnesses were reported among persons 65 years of age or older. Patients seemed to benefit from antiviral therapy.
1,586 citations
TL;DR: A critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus is demonstrated.
Abstract: Innate lymphoid cells (ILCs), a heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine, but whether ILCs influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed the alloantigen Thy-1 (CD90), interleukin 2 (IL-2) receptor a-chain (CD25), IL-7 receptor a-chain (CD127) and the IL-33 receptor subunit T1-ST2. Notably, mouse ILCs accumulated in the lung after infection with influenza virus, and depletion of ILCs resulted in loss of airway epithelial integrity, diminished lung function and impaired airway remodeling. These defects were restored by administration of the lung ILC product amphiregulin. Collectively, our results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus.
1,270 citations
TL;DR: Results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans are discussed and the extraordinary heterogeneity of asthma is described.
Abstract: Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (T(H)2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the T(H)17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.
1,268 citations