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Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1β, IL-23 and TGF-β. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents. Innate lymphoid cells (ILCs) play critical immunological roles including immune surveillance at mucosal sites. Here the authors show that during nasal inflammation pathogen-induced cytokine production guides the differentiation of ILCs.

Key Points Innate lymphoid cells (ILCs) are important for the orchestration of immune responses against pathogens and the maintenance of tissue homeostasis, processes mediated mainly by cytokine crosstalk between ILCs and various cell types ILCs play a role in the initiation and exacerbation of autoimmune responses through the amplification of the IL-23–IL-17 cytokine axis ILC3s are emerging as plausible therapeutic targets in rheumatic disease as they are present in autoimmune inflamed tissue and ILC3-derived cytokines enhance disease-inflammatory processes Despite improved understanding of the role of ILCs in chronic inflammation, the mechanisms by which ILC might influence rheumatic disease processes remain poorly characterized Innate lymphoid cells are important players in the innate immune response, and might also contribute to inflammatory diseases. This Review discusses what is known about these cells and how they might be targeted in future therapies for these diseases. Innate lymphoid cells (ILCs) are important in the regulation of barrier homeostasis. These cells do not express T cell receptors but share many functional similarities with T helper cells and cytotoxic CD8 + T lymphocytes. ILCs are divided into three groups, namely group 1 ILCs, group 2 ILCs and group 3 ILCs, based on the transcription factors they depend on for their development and function, and the cytokines they produce. Emerging data indicate that ILCs not only have protective functions but can also have detrimental effects when dysregulated, leading to chronic inflammation and autoimmune diseases, including asthma, inflammatory bowel disease, graft-versus-host disease, psoriasis, rheumatoid arthritis and atopic dermatitis. Elucidation of the cytokine pathways involved in various autoimmune diseases — and the identification of ILCs as potent producers of these cytokines — points towards a potential role for these cellular players in the pathophysiology of these diseases. In this Review we discuss the current knowledge of the role of ILCs in the pathogenesis of rheumatic and other autoimmune diseases.

Innate lymphoid cells (ILCs) are important for tissue homeostasis and for the initiation of immune responses. Based on their transcriptional regulation and cytokine profiles, ILCs can be categorized into five subsets with defined phenotypes and functional profiles, but they also have the ability to adapt to local environmental cues by changing these profiles. This plasticity raises the question of the extent to which the cytokine production profiles of ILCs are pre-programmed or are a reflection of the tissue microenvironment. Here, we review recent advances in research on ILCs, with a focus on the plasticity of these cells. We highlight the ability of ILCs to communicate with the surrounding microenvironment and discuss the possible consequences of ILC plasticity for our understanding of the biological roles of these cells. Finally, we discuss how we might use this knowledge of ILC plasticity to develop or improve options for the treatment of inflammatory diseases.Innate lymphoid cell (ILC) subsets with defined phenotypes can adapt to local environmental cues through transdifferentiation. Studies of such plasticity have improved our understanding of the biological roles of ILCs and offer promise for new strategies to treat inflammatory diseases and cancer.

Abstract Rationale Eosinophils drive pathophysiology in stable and exacerbating eosinophilic asthma, and therefore treatment is focused on the reduction of eosinophil numbers. Mepolizumab, a humanized monoclonal antibody that neutralizes IL-5 and efficiently attenuates eosinophils, proved clinically effective in severe eosinophilic asthma but not in mild asthma. Objectives To study the effect of mepolizumab on virus-induced immune responses in mild asthma. Methods Patients with mild asthma, steroid-naive and randomized for eosinophil numbers, received 750 mg mepolizumab intravenously in a placebo-controlled double-blind trial, 2 weeks after which patients were challenged with rhinovirus (RV) 16. FEV1, FVC, fractional exhaled nitric oxide, symptom scores (asthma control score), viral load (PCR), eosinophil numbers, humoral (luminex, ELISA), and cellular (flow cytometry) immune parameters in blood, BAL fluid, and sputum, before and after mepolizumab and RV16, were assessed. Measurements and Main Results Mepolizumab attenuated baseline blood eosinophils and their activation, attenuated trendwise sputum eosinophils, and enhanced circulating natural killer cells. Mepolizumab did not affect FEV1, FVC, and fractional exhaled nitric oxide, neither at baseline nor after RV16. On RV16 challenge mepolizumab did not prevent eosinophil activation but did enhance local B lymphocytes and macrophages and reduce neutrophils and their activation. Mepolizumab also enhanced secretory IgA and reduced tryptase in BAL fluid. Finally, mepolizumab affected particularly RV16-induced macrophage inflammatory protein-3a, vascular endothelial growth factor-A, and IL-1RA production in BAL fluid. Conclusions Mepolizumab failed to prevent activation of remaining eosinophils and changed RV16-induced immune responses in mild asthma. Although these latter effects likely are caused by attenuated eosinophil numbers, we cannot exclude a role for basophils. Clinical trial registered with www.clinicaltrials.gov (NCT 01520051).

Enhanced immunogenicity of subunit antigens can be achieved by antigen encapsulation in liposomes and the addition of immune potentiators. In this study we co-encapsulated ovalbumin (OVA) and a Toll-like receptor (TLR) ligand (PAM3CSK4 (PAM) or CpG) in cationic liposomes and investigated the effect of the formulations on dendritic cell (DC) maturation in vitro and on the immune response in mice after intradermal immunisation. Co-encapsulation of PAM did not affect the OVA content of the liposomes, but co-encapsulation of CpG led to a decrease in OVA content by 25%. After liposomal encapsulation, both ligands retained the ability to activate TLR-transfected HEK cells, though PAM only induced activation at elevated concentrations. DC maturation induced by liposome-based adjuvant formulations was superior compared to the free adjuvants. Encapsulation of PAM and CpG in liposomes did not influence the total IgG titres compared to the antigen/adjuvant solution, but OVA/CpG liposomes shifted the IgG1/IgG2a balance more to the direction of IgG2a compared to non-encapsulated CpG. Moreover, only this formulation resulted in IFN-γ production by restimulated splenocytes from immunised mice. These data show that co-encapsulation of antigen and immune potentiator in cationic liposomes, can affect the type of immune response generated after intradermal immunisation.

Transdifferentiation between group 1 and group 3 innate lymphoid cells (ILCs) has been observed in the gut. Spits and colleagues now show lung ILC2s are able to convert into ILC1s in an IL-12-dependent manner. Group 2 innate lymphoid cells (ILC2s) secrete type 2 cytokines, which protect against parasites but can also contribute to a variety of inflammatory airway diseases. We report here that interleukin 1β (IL-1β) directly activated human ILC2s and that IL-12 induced the conversion of these activated ILC2s into interferon-γ (IFN-γ)-producing ILC1s, which was reversed by IL-4. The plasticity of ILCs was manifested in diseased tissues of patients with severe chronic obstructive pulmonary disease (COPD) or chronic rhinosinusitis with nasal polyps (CRSwNP), which displayed IL-12 or IL-4 signatures and the accumulation of ILC1s or ILC2s, respectively. Eosinophils were a major cellular source of IL-4, which revealed cross-talk between IL-5-producing ILC2s and IL-4-producing eosinophils. We propose that IL-12 and IL-4 govern ILC2 functional identity and that their imbalance results in the perpetuation of type 1 or type 2 inflammation.

To provoke an immune response, a transcutaneously administered vaccine has to diffuse into the skin, reach the lymph nodes and be taken up by dendritic cells (DCs). To study these three steps we immunised mice transcutaneously (with microneedles), intradermally and intranodally. The effect of the formulation was investigated by formulating ovalbumin (OVA) in three ways with N-trimethyl chitosan (TMC): TMC + OVA mixtures, TMC–OVA conjugates and TMC/OVA nanoparticles. Both the percentage OVA + DCs in the lymph node and the resultant immunogenicity (serum IgG titres) were studied. Transcutaneously, the TMC–OVA conjugates induced the highest IgG levels and resulted in more OVA + DCs in the lymph nodes after 24 h than the other TMC formulations. Intradermally, all TMC-adjuvanted OVA formulations increased IgG titres compared to plain OVA. These formulations formed a depot in the skin, prolonging OVA delivery to the lymph nodes. The prolonged delivery of TMC-adjuvanted OVA to lymph node resident DCs was also observed after intranodal immunisation, but in this case the higher uptake did not correspond with elevated antibody titres compared to plain OVA. In conclusion, after transcutaneous administration, TMC–OVA conjugates are most immunogenic among the tested formulations, likely because they penetrate the skin more easily than nanoparticles and consequently are better delivered to DCs, while they show higher uptake by DCs than TMC + OVA mixtures.

Severe respiratory syncytial virus (RSV) disease is a frequent cause of acute respiratory distress syndrome (ARDS) in young children, and is associated with marked lung epithelial injury and neutrophilic inflammation. Experimental studies on ARDS have shown that inhibition of apoptosis in the lungs reduces lung epithelial injury. However, the blockade of apoptosis in the lungs may also have deleterious effects by hampering viral clearance, and importantly, by enhancing or prolonging local proinflammatory responses. The aim of this study was to determine the effect of the broad caspase inhibitor Z‐VAD(OMe)‐FMK (zVAD) on inflammation and lung injury in a mouse pneumovirus model for severe RSV disease. Eight‐ to 11‐week‐old female C57BL/6OlaHsd mice were inoculated with the rodent‐specific pneumovirus pneumonia virus of mice (PVM) strain J3666 and received multiple injections of zVAD or vehicle (control) during the course of disease, after which they were studied for markers of apoptosis, inflammation, and lung injury on day 7 after infection. PVM‐infected mice that received zVAD had a strong increase in neutrophil numbers in the lungs, which was associated with decreased neutrophil apoptosis. Furthermore, zVAD treatment led to higher concentrations of several proinflammatory cytokines in the lungs and more weight loss in PVM‐infected mice. In contrast, zVAD did not reduce apoptosis of lung epithelial cells and did not affect the degree of lung injury, permeability, and viral titers in PVM disease. We conclude that zVAD has an adverse effect in severe pneumovirus disease in mice by enhancing the lung proinflammatory response. Our research adds to the knowledge of the role of apoptosis in the pathogenesis of acute lung injury. Specifically, by exploiting a mouse model for severe respiratory syncytial virus disease, this work reveals that treatment with a caspase inhibitor has adverse effects in pneumoviral‐induced lung injury, by enhancing the local proinflammatory response without protecting from lung epithelial injury.

During persistent infection and hypoxic-stress, Mycobacterium tuberculosis ( Mtb) expresses a series of Mtb latency antigens. The aim of this study was to evaluate the immunogenicity of a DNA vaccine encoding the Mtb latency antigen Rv1733c and to explore the effect of pulmonary delivery and co-formulation with poly ( d, l-lactide- co-glycolide) (PLGA)–polyethyleneimine (PEI) nanoparticles (np) on host immunity. Characterization studies indicated that PLGA–PEI np kept their nanometer size after concentration and were positively charged. The np were able to mature human dendritic cells and stimulated them to secrete IL-12 and TNF-α comparable to levels observed after lipopolysaccharide (LPS) stimulation. Mtb latency antigen Rv1733c DNA prime combined with Rv1733c protein boost enhanced T cell proliferation and IFN-γ secretion in mice in response to Rv1733c and Mtb hypoxic lysate. Rv1733c DNA adsorbed to PLGA–PEI np and applied to the lungs increased T cell proliferation and IFN-γ production more potently compared to the same vaccinations given intramuscularly. The strongest immunogenicity was obtained by pulmonary priming with np-adsorbed Rv1733c DNA followed by boosting with Rv1733c protein. These results confirm that PLGA–PEI np are an efficient DNA vaccine delivery system to enhance T cell responses through pulmonary delivery in a DNA prime/protein boost vaccine regimen.