Type 2 cytokines (IL-4, IL-5, and IL-13) play a pivotal role in helminthic infection and allergic disorders. CD4+ T cells which produce type 2 cytokines can be generated via IL-4-dependent and -independent pathways. Although the IL-4-dependent pathway is well documented, factors that drive IL-4-independent Th2 cell differentiation remain obscure. We report here that the new cytokine IL-33, in the presence of Ag, polarizes murine and human naive CD4+ T cells into a population of T cells which produce mainly IL-5 but not IL-4. This polarization requires IL-1R-related molecule and MyD88 but not IL-4 or STAT6. The IL-33-induced T cell differentiation is also dependent on the phosphorylation of MAPKs and NF-κB but not the induction of GATA3 or T-bet. In vivo, ST2−/− mice developed attenuated airway inflammation and IL-5 production in a murine model of asthma. Conversely, IL-33 administration induced the IL-5-producing T cells and exacerbated allergen-induced airway inflammation in wild-type as well as IL-4−/− mice. Finally, adoptive transfer of IL-33-polarized IL-5+IL-4−T cells triggered airway inflammation in naive IL-4−/− mice. Thus, we demonstrate here that, in the presence of Ag, IL-33 induces IL-5-producing T cells and promotes airway inflammation independent of IL-4.

TLRs are primary sensors of both innate and adaptive immune systems, where they play a pivotal role in the response directed against structurally conserved components of pathogens. Synthetic bacterial lipopeptide Pam3CSK4 is a TLR2 agonist capable of modulating Th1 and Th2 responses. This study examines the therapeutic effect of Pam3CSK4 in established airway inflammation in a murine model of asthma. In mice previously sensitized and challenged with OVA, Pam3CSK4 given i.p. markedly reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid. Pam3CSK4 therapy was associated with a reduction in OVA-induced IL-4 and IL-5 secretion from thoracic lymph node culture, airways inflammation, bronchial hyperresponsiveness, and serum levels of IgE. Pam3CSK4 therapy was also associated with an increase in OVA-induced IFN-γ, IL-12, and IL-10 production. However, the anti-inflammatory effect of Pam3CSK4 was independent of IL-10 or TGF-β, but was critically dependent on IL-12, the production of which by dendritic cells was enhanced by Pam3CSK4 in vitro. Our results provide direct evidence that Pam3CSK4 could represent a novel therapeutic agent in allergic airways disease.

Glucocorticoid‐induced TNFR family‐related protein (GITR) is expressed at low levels on resting T cells, B cells and macrophages but at high levels on regulatory T cells (Treg). Although GITR expression is up‐regulated on CD4+ effector cells upon activation, the role of GITR in Th1 and Th2 cell development is unclear. We report here that activation of GITR signalling by anti‐GITR antibody markedly enhanced the induction of both Th1 and Th2 cytokine production by naive CD4+CD25– T cells. Consistent with this observation, anti‐GITR antibody significantly enhanced the expression of the key Th1 (T‐bet) and Th2 (GATA3) transcription factors in vitro. Administration of anti‐GITR mAb in a murine model of arthritis significantly exacerbated the severity and onset of joint inflammation with elevated production of TNF‐α, IFN‐γ, IL‐5, and collagen‐specific IgG1. Administration of anti‐GITR mAb also significantly exacerbated murine allergic airways inflammation with elevated production of OVA‐specific IFN‐γ, IL‐2, IL‐4, IL‐5, and IgE. Finally, we demonstrated that adoptive transfer of CD4+GITR+ T cells effectively abolished airway inflammation induced in SCID mice reconstituted with CD4+GITR– T cells. Our results therefore provide direct evidence that GITR can modulate both Th1‐ and Th2‐mediated inflammatory diseases, and may be a potential target for therapeutic intervention.

Background: Current guidelines recommend the use of a combination of inhaled b 2 agonists and anticholinergics, particularly for patients with acute severe or life threatening asthma in the emergency setting. However, this statement is based on a relatively small number of randomised controlled trials and related systematic reviews. A review was undertaken to incorporate the more recent evidence available about the effectiveness of treatment with a combination of b 2 agonists and anticholinergics compared with b 2 agonists alone in the treatment of acute asthma. Conclusions: This review strongly suggests that the addition of multiple doses of inhaled ipratropium bromide to b 2 agonists is indicated as the standard treatment in children, adolescents, and adults with moderate to severe exacerbations of asthma in the emergency setting.

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