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Influenza virus infection is an important cause of severe asthma exacerbations, but it remains unclear how a Th1-mediated antiviral response triggers a prototypical Th2 disease. We investigated CD4 + T cells and group 2 innate lymphoid cells (ILC2s) in influenza virus-infected mice. We found that ILC2s accumulated in the lung rapidly after influenza virus infection, but the induction of IL-5 and IL-13 secretion was delayed and concomitant with T cell activation. In an influenza-induced exacerbation of allergic airway inflammation model we noticed an initial reduction of ILC2 numbers and cytokine production in broncho-alveolar lavage compared to chronic house dust mite (HDM)-mediated airway inflammation alone. ILC2s phenotype was characterized by low T1/ST2, ICOS, KLRG1, and CD25 expression, resembling naïve ILC2s. The contribution of ILC2s to type 2 cytokine production in the early stage of the influenza-induced exacerbation was limited. In contrast, T cells showed increased IL-4 and IL-5 production when exposed to both HDM and influenza virus. Upon virus clearance, ILC2s regained an activated T1/ST2 high ICOS high KLRG1 high CD25 high phenotype paired with cytokine production and were major contributors to the type 2 cytokine milieu. Collectively, our data indicate that both T cells and ILC2s contribute to influenza-induced exacerbation of allergic airway inflammation, but with different kinetics., (© 2018 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Interleukin-17A (IL-17A) signals through the IL-17 receptor (IL-17R) A/C heterodimer. IL-17RA serves as a common receptor subunit for several IL-17 cytokine family members. Lack of IL-17RA signaling may therefore have additional effects beyond those of lack of IL-17A alone. The present study was undertaken to determine the role of IL-17RA signaling in autoimmune arthritis., Methods: Disease incidence and severity were scored in type II collagen-treated wild-type, IL-17RA-deficient, and IL-23p19-deficient mice. T helper cell profiles and humoral immune responses were analyzed at several time points. Pathogenicity of T cells and total splenocytes was determined by in vitro functional assay. IL-17RA signaling was blocked in vivo in mice with antigen-induced arthritis (AIA)., Results: Comparable to the findings in IL-23p19-deficient mice, IL-17RA-deficient mice were completely protected against the development of collagen-induced arthritis (CIA). However, IL-17RA-deficient mice exhibited an increased number of IL-4-producing CD4+ T cells, distinct from IL-17A+CD4+ T cells. This was associated with fewer plasma cells, lower production of pathogenic IgG2c antibody, and increased production of IgG1 antibody. Both isolated CD4+ T cells and total splenocytes from IL-17RA-deficient mice had a reduced ability to induce IL-6 production by synovial fibroblasts in the setting of CIA, in a functional in vitro assay. Furthermore, blocking of IL-17RA signaling in AIA reduced synovial inflammation., Conclusion: These results demonstrate that absence of IL-17RA leads to a Th2-like phenotype characterized by IL-4 production and suggest that IL-17RA signaling plays a critical role in the regulation of IL-4 in CIA and the development of autoimmune inflammation of the joint., (Copyright © 2014 by the American College of Rheumatology.)

Background: Allergic rhinitis (AR) and asthma often coexist and are referred to as 'united airways' disease. However, the molecular and cellular pathways that are crucially involved in the interaction between upper and lower airways remain to be identified., Objective: We sought to assess whether and how AR exacerbates lower airway inflammation upon allergen challenge in mice., Methods: We previously developed an intranasal ovalbumin (OVA)-driven AR model, characterized by nasal eosinophilic inflammation, enhanced serum levels of OVA-specific IgE and Th2 cytokine production in cervical lymph nodes. In OVA-sensitized mice with or without AR, a lower airway challenge was given, and after 24 h, lower airway inflammation was analysed., Results: We found that AR mice were more susceptible to eosinophilic inflammation following a lower airway OVA challenge than OVA-sensitized controls. AR mice manifested increased numbers of eosinophils in bronchoalveolar lavage fluid and increased inter-cellular adhesion molecule-1 (ICAM-1) expression on lung endothelium, when compared with OVA-sensitized controls. Depletion of T cells in OVA-challenged AR mice completely abrogated all hallmarks of lower airway inflammation, including enhanced IL-5 and tissue eosinophilia. Conversely, adoptive transfer of Th2 effector cells in naïve animals induced lower airway eosinophilic inflammation after challenge with OVA. Blocking T cell recirculation during AR development by the spingosine-1 analogue FTY720 also prevented lower airway inflammation including ICAM-1 expression in AR mice upon a single lower airway challenge., Conclusion: Our mouse model of 'united airways' disease supports epidemiological and clinical data that AR has a significant impact on lower airway inflammation. Circulating Th2 effector cells are responsible for lung priming in AR mice, most likely through up-regulation of ICAM-1.

It was previously shown that administration of recombinant human Fms-like tyrosine kinase receptor-3 ligand (Flt3L) before allergen challenge of sensitized mice suppresses the cardinal features of asthma through unclear mechanisms. Here, we show that Flt3L dramatically alters the balance of conventional to plasmacytoid dendritic cells (pDCs) in the lung favoring the accumulation of pDCs. Selective removal of pDCs abolished the antiinflammatory effect of Flt3L, suggesting a regulatory role for these cells in ongoing asthmatic inflammation. In support, we found that immature pDCs are recruited to the lungs of allergen-challenged mice irrespective of Flt3L treatment. Selective removal of pDCs during allergen challenge enhanced airway inflammation, whereas adoptive transfer of cultured pDCs before allergen challenge suppressed inflammation. Experiments in which TLR9 agonist CpG motifs were administered in vitro or in vivo demonstrated that pDCs were antiinflammatory irrespective of their maturation state. These effects were mediated through programmed death-1/programmed death ligand 1 interactions, but not through ICOS ligand, IDO, or IFN-alpha. These findings suggest a specialized immunoregulatory role for pDCs in airway inflammation. Enhancing the antiinflammatory properties of pDCs could be employed as a novel strategy in asthma treatment.

Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines, but the mechanism of its adjuvanticity remains unknown. In vitro studies showed no stimulatory effects on dendritic cells (DCs). In the absence of adjuvant, Ag was taken up by lymph node (LN)-resident DCs that acquired soluble Ag via afferent lymphatics, whereas after injection of alum, Ag was taken up, processed, and presented by inflammatory monocytes that migrated from the peritoneum, thus becoming inflammatory DCs that induced a persistent Th2 response. The enhancing effects of alum on both cellular and humoral immunity were completely abolished when CD11c(+) monocytes and DCs were conditionally depleted during immunization. Mechanistically, DC-driven responses were abolished in MyD88-deficient mice and after uricase treatment, implying the induction of uric acid. These findings suggest that alum adjuvant is immunogenic by exploiting "nature's adjuvant," the inflammatory DC through induction of the endogenous danger signal uric acid.

In healthy individuals, humoral immune responses to allergens consist of serum IgA and IgG4, whereas cellular immune responses are controlled by regulatory T (Treg) cells. In search of new compounds that might prevent the onset of allergies by stimulating this type of immune response, we have focused on the mucosal adjuvant, cholera toxin B (CTB), as it induces the formation of Treg cells and production of IgA. Here, we have found that CTB suppresses the potential of dendritic cells to prime for Th2 responses to inhaled allergen. When we administered CTB to the airways of naïve and allergic mice, it strongly suppressed the salient features of asthma, such as airway eosinophilia, Th2 cytokine synthesis, and bronchial hyperreactivity. This beneficial effect was only transferable to other mice by transfer of B but not of T lymphocytes. CTB caused a transforming growth factor-β-dependent rise in antigen-specific IgA in the airway luminal secretions, which was necessary for its preventive and curative effect, as all effects of CTB were abrogated in mice lacking the luminal IgA transporting polymeric Ig receptor. Not only do these findings show a novel therapeutic avenue for allergy, they also help to explain the complex relationship between IgA levels and risk of developing allergy in humans.Mucosal Immunology (2009) 2, 331–339; doi:10.1038/mi.2009.16; published online 29 April 2009 [ABSTRACT FROM AUTHOR]