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• Adaptive regulatory T (Treg) cells are associated with tolerance to milk allergen
• Targeting cytokines in experimental food allergy
• IL-17–mediated host defense is partially impaired in patients with atopic eczema
• CCR4 leads the way for TH2 cell homing into the allergic lung
• Mast cells as antigen-presenting cells
• HLX1 gene variants influence the development of childhood asthma
• Copyright

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Adaptive regulatory T (Treg) cells are associated with tolerance to milk allergen 

CD25^hi FoxP3⁺ regulatory T (Treg) cells have been implicated in both self-tolerance and the regulation of antigen-specific immunity, including tolerance to food allergens. Shreffler et al (p 43) have now provided the strongest evidence to date that the resolution of milk allergy in children might be due to the expansion of milk allergen–specific Treg cells. On the basis of observations that milk-allergic children who tolerate heat-denatured dietary milk protein have a more restricted allergen-specific IgE repertoire and higher levels of specific IgG4 and outgrow their milk allergy earlier, the authors hypothesized that those patients would have a higher frequency of specific regulatory cells. To test this, they measured the allergen-induced expansion of effector and Treg cells by carboxyfluorescein succinimidyl ester dilution and polychromatic flow cytometry. Patients tolerant of heated milk had significantly higher frequencies of Treg, but not effector, cells. These cells expressed low levels of CD127 and high levels of CD25, CD27, FoxP3, and cytotoxic T lymphocyte–associated antigen 4. By comparing expansion with or without predepletion, the authors demonstrated that the Treg cells are both expanded from the circulating CD25^hi population and functionally suppressive (see Figure).

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• Expansion of specific Treg or effector cells with (orange histograms, C⁺) or without (blue, C^–) CD25^hi cells at baseline.

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Targeting cytokines in experimental food allergy 

Oral allergen–induced diarrhea is triggered by a local anaphylactic reaction resulting from IgE-mediated mast cell release of serotonin and platelet-activating factor. In this issue, Brandt et al (p 53) dissect the respective contribution of the T_H2 cytokines IL-4 and IL-13 in disease pathogenesis using mice genetically deficient in IL-4, IL-13, both IL-4 and IL-13, or the IL-13 receptor (R) α1 chain. Both IL-4 and IL-13 were shown to contribute to the sensitization phase rather than the effector phase of the disease by regulating IgE production. Blocking IL-4 and IL-13 receptors with an antibody directed against the shared receptor unit IL-4Rα had no immediate impact on established disease, but prophylactic usage inhibited the development of allergic diarrhea (see Figure). These results establish the potential utility of inhibitors of IL-4 and/or IL-13 in gastrointestinal allergic responses.

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• Allergen-induced diarrhea (A) and intestinal mast cell levels (B) in antibody-treated Balb/c mice (5 per group).

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IL-17–mediated host defense is partially impaired in patients with atopic eczema 

IL-17 is an important stimulus for the induction of antimicrobial peptides (defensins) in the skin and is therefore crucial in the first-line defense of the organism. Almost 100% of patients with atopic eczema (AE) suffer from a disease-relevant skin colonization with Staphylococcus aureus, most likely due to a diminished production of defensins. Eyerich et al (p 59) show in the current study that IL-17–producing T cells infiltrate acute AE reactions—in particular, the newly characterized subtype T_H2/IL-17 cells. Interestingly, T cells challenged with their cognate allergen did not produce IL-17 in vitro, but IL-17 secretion could be triggered by staphylococcal-derived enterotoxins frequently present on AE skin. In a second step, the authors show that the inefficient defensin induction is due not to an intrinsic defect in AE keratinocytes but rather to counteracting effects of T_H2 cytokines like IL-4 and IL-13. This study provides insights in the importance of the skin microenvironment for the outcome of (T-cell) mediated immune responses. Furthermore, it is of clinical relevance, as it underlines the importance of early and consequent therapy of skin lesions to avoid insufficient and persistent triggering of the IL-17/human β-defensin 2 axis in ongoing acute AE.

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CCR4 leads the way for T_H2 cell homing into the allergic lung 

The recruitment of T_H2 cells into the airway is crucial in asthma pathogenesis and is mediated to a large extent by chemokine receptors expressed on T_H2 cells and signal transducer and activator of transcription 6–inducible chemokines produced in the lung. There is a preponderance of indirect evidence implicating CC chemokine receptor 4 (CCR4) and CCR8 in T_H2 cell trafficking in asthma. CD4⁺ T cells that infiltrate the asthmatic lung express CCR4 and CCR8, and the chemokine ligands for these receptors are increased in the airways of asthmatics. However, the relative contribution of these receptors to T_H2 cell homing into the allergic lung has not been defined. As reported in this issue of the Journal, Mikhak et al (p 67) used antigen-specific T_H2 cells deficient in CCR4 or CCR8 in an adoptive transfer model of asthma to demonstrate that CCR4 was required for efficient trafficking of T_H2 cells into the allergic airway, whereas CCR8 was not. Surprisingly, CCR8 deficiency resulted in increased accumulation of T_H2 cells in the allergic lung. In the absence of CCR4, there was a dramatic decline in airway T_H2-type cytokines (see Figure) and eosinophils. Nevertheless, the residual T_H2-type cytokines were sufficient to preserve some markers of allergic lung inflammation, including airway hyperresponsiveness. These findings suggest that inhibition of CCR4-mediated T_H2 cell trafficking might contribute to asthma therapy.

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• Interruption of CCR4-mediated T_H2 cell trafficking dramatically decreases T_H2-type cytokines in the airway.

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Mast cells as antigen-presenting cells 

Mast cells are recognized as crucial effector cells in IgE-dependent immune responses and as initiators and effectors in innate immune responses to pathogens. In addition, it is known that mast cells play important roles in the development of several T cell–mediated diseases, including delayed-type contact hypersensitivity, asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. Although these matters indicate that mast cells are involved in the initiation of adaptive immune responses, the mechanisms of mast cell–T cell interactions have not been fully resolved. In this study, Nakano et al (p 74) showed that mouse mast cells constitutively expressed Notch1 and Notch2 receptors and that the stimulation with a Notch ligand Delta-like 1 (Dll1) induced the expressions of a class II major histocompatibility complex and a costimulatory molecule OX40 ligand on the mast cells. The bone marrow–derived mast cells stimulated with Dll1 activated antigen-specific CD4⁺ T cells by direct interaction (see Figure) and induced the differentiation of T_H2. The finding that mast cells acquired antigen-presenting cell functions by Dll1/Notch signaling will contribute to the elucidation of the pathogenic mechanism of allergic disorders and several T cell–mediated diseases.

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• Dll1-stimulated bone marrow–derived mast cells (Dll1-BMMCs) activated antigen-specific CD4⁺ T cells by direct interaction.

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HLX1 gene variants influence the development of childhood asthma 

Asthma and atopic diseases may be viewed as syndromes rather than clear-cut disease entities, and genetics may help us to better dissect mechanisms leading to the onset of these diseases. Genome-wide association studies (GWASs) have already changed genetics of complex diseases and will also change our understanding of asthma and allergies in the future. Yet, however powerful, GWASs cannot capture the complete picture, as many genes and pathways may interact and modify asthma; if you do not know where to look, you may miss important pieces of the picture. The work by Suttner and colleagues (p 82), published in this issue, takes a close look at the genetic effect of polymorphisms in a T cell–associated transcription factor on allergy and asthma. On the basis of previously acquired biological evidence, they studied homeobox factor 1 (HLX1), which interacts with T-bet to optimize T_H1 differentiation. Resequencing the whole HLX1 gene locus and genotyping large population samples of German children, they identified polymorphisms that increased asthma risk by almost 50%. Their in vitro functional studies suggest that promoter polymorphisms in the gene might be involved in these effects, again pointing to the importance of T cells in the onset of asthma.