Expression of ICOS In Vivo Defines CD4+ Effector T Cells with High Inflammatory Potential and a Strong Bias for Secretion of Interleukin 10

The studies performed to date analyzed the overall participation of the inducible costimulator (ICOS) in model diseases, but did not yield information on the nature and function of ICOS-expressing T cells in vivo. We examined ICOS+ T cells in the secondary lymphoid organs of nonmanipulated mice, in the context of an “unbiased” immune system shaped by environmental antigens. Using single cell analysis, ICOSlow cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-γ. ICOSmedium cells, the large majority of ICOS+ T cells in vivo, were very tightly associated with the synthesis of the T helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatory effects in vivo. In contrast, ICOShigh T cells were highly and selectively linked to the anti-inflammatory cytokine IL-10. Overall, these data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties. Further in vivo functional experiments with in vitro–activated T cells strongly suggested that the ICOS+ population, although representing in vivo only around 10% of T cells bearing early or late activation markers, nevertheless encompasses virtually all effector T cells, a finding with major diagnostic and therapeutic implications

Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth

Bone growth requires a specialised, highly angiogenic blood vessel subtype, so-called type H vessels, which pave the way for osteoblasts surrounding these vessels. At the end of adolescence, type H vessels differentiate into quiescent type L endothelium lacking the capacity to promote bone growth. Until now, the signals that switch off type H vessel identity and thus limit adolescent bone growth have remained ill defined. Here we show that mechanical forces, associated with increased body weight at the end of adolescence, trigger the mechanoreceptor PIEZO1 and thereby mediate enhanced production of the kinase FAM20C in osteoblasts. FAM20C, the major kinase of the secreted phosphoproteome, phosphorylates dentin matrix protein 1, previously identified as a key factor in bone mineralization. Thereupon, dentin matrix protein 1 is secreted from osteoblasts in a burst-like manner. Extracellular dentin matrix protein 1 inhibits vascular endothelial growth factor signalling by preventing phosphorylation of vascular endothelial growth factor receptor 2. Hence, secreted dentin matrix protein 1 transforms type H vessels into type L to limit bone growth activity and enhance bone mineralization. The discovered mechanism may suggest new options for the treatment of diseases characterised by aberrant activity of bone and vessels such as osteoarthritis, osteoporosis and osteosarcoma

IL1RL1 Gene Variants and Nasopharyngeal IL1RL-a Levels Are Associated with Severe RSV Bronchiolitis: A Multicenter Cohort Study

Targets for intervention are required for respiratory syncytial virus (RSV) bronchiolitis, a common disease during infancy for which no effective treatment exists. Clinical and genetic studies indicate that IL1RL1 plays an important role in the development and exacerbations of asthma. Human IL1RL1 encodes three isoforms, including soluble IL1RL1-a, that can influence IL33 signalling by modifying inflammatory responses to epithelial damage. We hypothesized that IL1RL1 gene variants and soluble IL1RL1-a are associated with severe RSV bronchiolitis.We studied the association between RSV and 3 selected IL1RL1 single-nucleotide polymorphisms rs1921622, rs11685480 or rs1420101 in 81 ventilated and 384 non-ventilated children under 1 year of age hospitalized with primary RSV bronchiolitis in comparison to 930 healthy controls. Severe RSV infection was defined by need for mechanical ventilation. Furthermore, we examined soluble IL1RL1-a concentration in nasopharyngeal aspirates from children hospitalized with primary RSV bronchiolitis. An association between SNP rs1921622 and disease severity was found at the allele and genotype level (p = 0.011 and p = 0.040, respectively). In hospitalized non-ventilated patients, RSV bronchiolitis was not associated with IL1RL1 genotypes. Median concentrations of soluble IL1RL1-a in nasopharyngeal aspirates were >20-fold higher in ventilated infants when compared to non-ventilated infants with RSV (median [and quartiles] 9,357 [936-15,528] pg/ml vs. 405 [112-1,193] pg/ml respectively; p<0.001).We found a genetic link between rs1921622 IL1RL1 polymorphism and disease severity in RSV bronchiolitis. The potential biological role of IL1RL1 in the pathogenesis of severe RSV bronchiolitis was further supported by high local concentrations of IL1RL1 in children with most severe disease. We speculate that IL1RL1a modifies epithelial damage mediated inflammatory responses during RSV bronchiolitis and thus may serve as a novel target for intervention to control disease severity

Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection

The molecular mechanisms that drive mucosal T helper type 2 (T[subscript H]2) responses against parasitic helminths and allergens remain unclear. In this study, we demonstrate in mice that TFF2 (trefoil factor 2), an epithelial cell–derived repair molecule, is needed for the control of lung injury caused by the hookworm parasite Nippostrongylus brasiliensis and for type 2 immunity after infection. TFF2 is also necessary for the rapid production of IL-33, a T[subscript H]2-promoting cytokine, by lung epithelia, alveolar macrophages, and inflammatory dendritic cells in infected mice. TFF2 also increases the severity of allergic lung disease caused by house dust mite antigens or IL-13. Moreover, TFF2 messenger RNA expression is significantly increased in nasal mucosal brushings during asthma exacerbations in children. These experiments extend the biological functions of TFF2 from tissue repair to the initiation and maintenance of mucosal T[subscript H]2 responses

An epigenome-wide association study of total serum immunoglobulin E concentration

Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations-with a meta-analysis false discovery rate less than 10(-4)-between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases