Suzanne M. Bal

IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs

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.

Towards tailored vaccine delivery: Needs, challenges and perspectives

The ideal vaccine is a simple and stable formulation which can be conveniently administered and provides life-long immunity against a given pathogen. The development of such a vaccine, which should trigger broad and strong B-cell and T-cell responses against antigens of the pathogen in question, is highly dependent on tailored vaccine delivery approaches. This review addresses vaccine delivery in its broadest scope. We discuss the needs and challenges in the area of vaccine delivery, including restrictions posed by specific target populations, potentials of dedicated stable formulations and devices, and the use of adjuvants. Moreover, we address the current status and perspectives of vaccine delivery via several routes of administration, including non- or minimally invasive routes. Finally we suggest possible directions for future vaccine delivery research and development.

Innate lymphoid cells in autoimmunity: emerging regulators in rheumatic 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.

Neuropilin-1 Is Expressed on Lymphoid Tissue Residing LTi-like Group 3 Innate Lymphoid Cells and Associated with Ectopic Lymphoid Aggregates

Summary Here, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin. NRP1+ group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity. In agreement with this, NRP1+ ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs. NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells. Human NRP1+ ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1− cells, which express CD45RA. The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1+ ILC3s. NRP1+ ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates.

An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5-responsive mouse model

Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics.

The caspase inhibitor zVAD increases lung inflammation in pneumovirus infection in mice

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.

New insights into the function, development, and plasticity of type 2 innate lymphoid cells

Group 2 innate lymphoid cells (ILC2s) are the most well defined group of ILCs. ILC2 development is controlled by the GATA‐3 transcription factor and these cells produce archetypal type 2 cytokines, such as IL‐5 and IL‐13. These cytokines mediate parasite expulsion and tissue repair, but also contribute to type 2 inflammatory diseases, including allergy, asthma and chronic rhinosinusitis with nasal polyps. In response to tightly regulated local environmental cues ILCs can generate characteristics of other subtypes, a process known as plasticity. Recent advances in the ILC2 field has led to the discovery that ILC2s can promptly shift to functional IFN‐γ‐producing ILC1s or IL‐17‐producing ILC3s, depending on the cytokines and chemokines produced by antigen presenting cells or epithelial cells. Due to yet unknown triggers, this complex network of signals may become dysregulated. In this review, we will discuss general ILC characteristic, ILC2 development, plasticity, memory function, and implications in disease.

Interferon-induced epithelial response to rhinovirus-16 in asthma relates to inflammation and FEV1

Bronchial epithelial cells from mild asthma patients in response to in vivo rhinovirus-16 challenge, display a marked interferon-induced response 6 days post-infection, which correlates with eosinophilic inflammation and virus-induced decline of lung function.

Isolation of Human Innate Lymphoid Cells

Innate lymphoid cells (ILCs) are innate immune cells of lymphoid origin that have important effector and regulatory functions in the first line of defense against pathogens, but also regulate tissue homeostasis, remodeling, and repair. Their function mirrors T helper cells and cytotoxic CD8+ T lymphocytes, but they lack expression of rearranged antigen‐specific receptors. Distinct ILC subsets are classified in group 1 ILCs (ILC1s), group 2 ILCs (ILC2s), and group 3 ILCs (ILC3s and lymphoid tissue–inducer cells), based on the expression of transcription factors and the cytokines they produce. As the frequency of ILCs is low, their isolation requires extensive depletion of other cell types. The lack of unique cell surface antigens further complicates the identification of these cells. Here, methods for ILC isolation and characterization from human peripheral blood and different tissues are described.

IL33 and TSLP involvements in influenza-induced exacerbation in a murine model of chronic asthma

Introduction: Viral airway infections cause acute worsening of asthma symptoms and additional accumulation of inflammatory cell subsets in the airways. Here we aimed to dissect the innate immune response that might underlie virus-induced exacerbations in an adequate murine model of exacerbating asthma.nnMethods: Mice were sensitized i.n. to HDM extract for 5 days/week for 5 consecutive weeks. On day 29 mice were infected with low dose of influenza A/X31; 3 day before and after the virus infection the animals have been treated with anti TSLP and IL33 receptors (T1/ST2 and TSLPR, respectively) mAbs. The airways cellular influx was assessed, cytokines were measured in BALF, lung function and histology were determined in different time points after infection.nnResults: Infected sensitized mice infected showed an exacerbation of allergic inflammation as reflected by a prolonged AHR and a boosted inflammatory influx into the airways, in comparison to infected non-sensitized mice. As an early event upon influenza infection, sensitized mice showed the induction of IL-33 and TSLP paralleled by the increased influx into the airways of ILC2, basophils, NK and NKT cells. Blocking the effect of IL-33 and TSLP using anti T1/ST2 and TSLPR mAbs the NKT cells, basophils, ILC2 recruitments into the airways were attenuated; the eosinophilic and neutrophilic influxes were reduced in BALF.nnConclusions: Influenza infection of sensitized mice boosted the induction of crucial effectors of the innate immune response, leading the worsening of a broad inflammatory response into the airways.nnLimiting IL33 and TSLP can dampen airway inflammation and virus-induced changes in HDM-sensitized mice.