Neonatal mucosal immunology.

Although largely deprived from exogenous stimuli in utero, the mucosal barriers of the neonate after birth are bombarded by environmental, nutritional, and microbial exposures. The microbiome is established concurrently with the developing immune system. The nature and timing of discrete interactions between these two factors underpins the long-term immune characteristics of these organs, and can set an individual on a trajectory towards or away from disease. Microbial exposures in the gastrointestinal and respiratory tracts are some of the key determinants of the overall immune tone at these mucosal barriers and represent a leading target for future intervention strategies. In this review, we discuss immune maturation in the gut and lung and how microbes have a central role in this process.

Thymic stromal lymphopoietin plays divergent roles in murine models of atopic and nonatopic airway inflammation.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine primarily produced by epithelial cells, which has been shown to be a potent inducer of T-helper 2 (Th2)-type responses. However, TSLP has pleiotropic effects upon immune cells, and although extensively studied in the context of atopic asthma, its relevance as a therapeutic target and its role in the pathogenesis of nonatopic asthma remains unknown. We sought to investigate the role of TSLP in atopic, nonatopic and viral-induced exacerbations of pulmonary inflammation. METHODS: Using stringently defined murine models of atopic, nonatopic and virally exacerbated forms of pulmonary inflammation, we compared inflammatory responses of C57BL/6 wild-type (WT) and TSLP receptor-deficient (TSLPR KO) mice. RESULTS: Thymic stromal lymphopoietin receptor (TSLPR) signaling was crucial for the development of atopic asthma. Specifically, TSLPR signaling to lung recruited CD4+ T cells enhanced eosinophilia, goblet cell hyperplasia, and overall inflammation within the airways. In contrast, the absence of TSLPR signaling was associated with strikingly exaggerated pulmonary neutrophilic inflammation in a nonatopic model of airway inflammation. The inflammation was associated with excessive levels of interleukin (IL)-17A in the lungs, indicating that TSLP negatively regulates IL-17A. In addition, in a model of influenza-induced exacerbation of atopic airway inflammation, the absence of TSLPR signaling also led to exaggerated neutrophilic inflammation. CONCLUSION: Thymic stromal lymphopoietin plays divergent roles in the pathogenesis of atopic and nonatopic asthma phenotypes by either enhancing Th2 responses or curtailing T-helper 17 responses. These findings raise important caveats for the design of therapeutic interventions targeting TSLP in asthma.

TSLP promotes influenza-specific CD8+ T-cell responses by augmenting local inflammatory dendritic cell function.

Thymic stromal lymphopoietin (TSLP) is a mucosal tissue-associated cytokine that has been widely studied in the context of T helper type 2 (Th2)-driven inflammatory disorders. Although TSLP is also produced upon viral infection in vitro, the role of TSLP in antiviral immunity is unknown. In this study we report a novel role for TSLP in promoting viral clearance and virus-specific CD8+ T-cell responses during influenza A infection. Comparing the immune responses of wild-type and TSLP receptor (TSLPR)-deficient mice, we show that TSLP was required for the expansion and activation of virus-specific effector CD8+ T cells in the lung, but not the lymph node. The mechanism involved TSLPR signaling on newly recruited CD11b+ inflammatory dendritic cells (DCs) that acted to enhance interleukin-15 production and expression of the costimulatory molecule CD70. Taken together, these data highlight the pleiotropic activities of TSLP and provide evidence for its beneficial role in antiviral immunity.

Update in clinical allergy and immunology.

In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field.

Allergic airway inflammation is exacerbated during acute influenza infection and correlates with increased allergen presentation and recruitment of allergen-specific T-helper type 2 cells.

BACKGROUND: Respiratory viral infections are a leading cause of the hospitalization of asthmatics, however, the cellular immunological interactions which underlie these two diseases remain elusive. OBJECTIVE: We sought to characterize the effect influenza viral infection has on allergic airway inflammation and to identify the cellular pathways involved. METHODS: We have used an ovalbumin (OVA) model of allergic airway inflammation, which involves sensitization of animals with OVA adsorbed in alum adjuvant followed by an intranasal challenge with OVA in phosphate-buffered saline. To study T cell recruitment into the lung, we adoptively transferred in vitro activated T cell receptor-transgenic T cells, which were subsequently identified by fluorescence-activated cell sorting (FACS) analysis. In addition, to study in vivo dendritic cell (DC) migration, we administered fluorescently labelled dextran and identified DCs that had phagocytosed it by FACS analysis. RESULTS: We found that different stages of influenza infection had contrasting effects upon the outcome of OVA-induced allergic airway inflammation. The allergic response against OVA was exacerbated during the acute stage of influenza infection; however, mice were protected against the development of airway eosinophilia at late time-points following infection. We investigated the mechanisms responsible for the virus-induced exacerbation and found that the response was partially independent of IL-4 and that there was increased delivery of inhaled allergens to the draining lymph node during the acute stage of the infection. In addition, virus-induced inflammation in the lung and draining lymph node resulted in the non-specific recruitment of circulating allergen-specific effector/memory cells. CONCLUSION: In addition to virus-mediated damage to the lung and airways, influenza viral infection can also enhance unrelated local allergic responses.

Construction of a recombinant orf virus that expresses an Echinococcus granulosus vaccine antigen from a novel genomic insertion site.

The potential of recombinant poxviruses as expression vectors has been extensively studied using Vaccinia virus but there has been only limited transfer of this technology to the Parapoxvirus genus. We detail here the construction of a recombinant Orf virus that expresses an antigenic peptide (EG95) of the causative agent of cystic hydatid disease, Echinococcus granulosus. Expression of this foreign antigen was regulated by a synthetic early/late poxvirus transcriptional promoter and levels of expression comparable to that achieved by a similar vaccinia virus recombinant were observed. The expression cassette was inserted into a unique orf virus gene (G1L) thereby confirming the non-essential nature of that gene and identifying a novel genomic insertion site. This recombinant will be a valuable tool with which to assess the potential of recombinant orf viruses to deliver vaccine antigens to sheep.