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Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3+ Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis. Dendritic cells play intricate roles in engaging a range of immune cells. Here, the authors establish a role for the transcription factor RelB in dendritic cells as a molecular rheostat that controls the level of immune tolerance by limiting the number of regulatory T cells. [ABSTRACT FROM AUTHOR]

Background: The rise in asthma has been linked to different environmental and lifestyle factors including dietary habits. Whether dietary salt contributes to asthma incidence, remains controversial. We aimed to investigate the impact of higher salt intake on asthma incidence in humans and to evaluate underlying mechanisms using mouse models. Methods: Epidemiological research was conducted using the UK Biobank Resource. Data were obtained from 42,976 participants with a history of allergies. 24‐h sodium excretion was estimated from spot urine, and its association with asthma incidence was assessed by Cox regression, adjusting for relevant covariates. For mechanistic studies, a mouse model of mite‐induced allergic airway inflammation (AAI) fed with high‐salt diet (HSD) or normal‐salt chow was used to characterize disease development. The microbiome of lung and feces (as proxy for gut) was analyzed via 16S rRNA gene based metabarcoding approach. Results: In humans, urinary sodium excretion was directly associated with asthma incidence among females but not among males. HSD‐fed female mice displayed an aggravated AAI characterized by increased levels of total IgE, a TH2‐TH17‐biased inflammatory cell infiltration accompanied by upregulation of osmosensitive stress genes. HSD induced distinct changes in serum short chain fatty acids and in both gut and lung microbiome, with a lower Bacteroidetes to Firmicutes ratio and decreased Lactobacillus relative abundance in the gut, and enriched members of Gammaproteobacteria in the lung. Conclusions: High dietary salt consumption correlates with asthma incidence in female adults with a history of allergies. Female mice revealed HSD‐induced T‐cell lung profiles accompanied by alterations of gut and lung microbiome. [ABSTRACT FROM AUTHOR]

Th subsets are defined according to their production of lineage-indicating cytokines and functions. In this study, we have identified a subset of human Th cells that infiltrates the epidermis in individuals with inflammatory skin disorders and is characterized by the secretion of IL-22 and TNF-α, but not IFN-γ, IL-4, or IL-17. In analogy to the Th17 subset, cells with this cytokine profile have been named the Th22 subset. Th22 clones derived from patients with psoriasis were stable in culture and exhibited a transcriptome profile clearly separate from those of Th1, Th2, and Th17 cells; it included genes encoding proteins involved in tissue remodeling, such as FGFs, and chemokines involved in angiogenesis and fibrosis. Primary human keratinocytes exposed to Th22 supernatants expressed a transcriptome response profile that included genes involved in innate immune pathways and the induction and modulation of adaptive immunity. These proinflammatory Th22 responses were synergistically dependent on IL-22 and TNF-α. Furthermore, Th22 supernatants enhanced wound healing in an in vitro injury model, which was exclusively dependent on IL-22. In conclusion, the human Th22 subset may represent a separate T cell subset with a distinct identity with respect to gene expression and function, present within the epidermal layer in inflammatory skin diseases. Future strategies directed against the Th22 subset may be of value in chronic inflammatory skin disorders., Introduction Th subsets play a discriminative role in translating antigen-specific immune responses into tissue functions or immunopathology. The identification of novel T cell subsets, such as Th17 cells, is important [...]

Background: Children with asthma have impaired production of interleukin (IL) 37; in mice, IL‐37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL‐37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL‐37 controls allergic inflammation. Methods: IL‐37 target cells were identified by single‐cell RNA‐seq of IL‐1R5 and IL‐1R8. Airway tissues were isolated by laser‐capture microdissection and examined by microarray‐based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL‐1β, or IL‐33 together with recombinant human (rh) IL‐37. Wild‐type, IL‐1R1– and IL‐33–deficient mice with EAA were treated with rhIL‐37. IL‐1β, IL‐33, and IL‐37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy. Results: IL‐37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL‐37 led to differential expression of >90 genes induced by IL‐1β and IL‐33. rhIL‐37 reduced production of Th2 cytokines in allergen‐activated MNCs from wild‐type but not from IL‐1R1–deficient mice and inhibited IL‐33–induced Th2 cytokine release. Furthermore, rhIL‐37 attenuated IL‐1β– and IL‐33–induced pro‐inflammatory mediator expression in murine AEC cultures. In contrast to wild‐type mice, hIL‐37 had no effect on EAA in IL‐1R1– or IL‐33–deficient mice. We also observed that expression/production ratios of both IL‐1β and IL‐33 to IL‐37 were dramatically increased in asthma patients compared to healthy controls. Conclusion: IL‐37 downregulates allergic airway inflammation by counterbalancing the disease‐amplifying effects of IL‐1β and IL‐33. [ABSTRACT FROM AUTHOR]

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 and Th17 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β is a major player in AAI by driving effector T cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the gene encoding for TGFβ-receptor 2 (Tgfbr2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of pro-inflammatory T cell frequencies (Th2, Th9, Th17), but increased Treg cells. To translate these findings into a human clinically relevant context, Th2, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9, and reduced Tregs cells, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs cells. [ABSTRACT FROM AUTHOR]

The pathophysiology of atopic dermatitis (AD) is highly complex and understanding of disease endotypes may improve disease management. Immunoglobulins E (IgE) against human skin epitopes (IgE autoantibodies) are thought to play a role in disease progression and prolongation. These antibodies have been described in patients with severe and chronic AD, suggesting a progression from allergic inflammation to severe autoimmune processes against the skin. This review provides a summary of the current knowledge and gaps on IgE autoreactivity and self-reactive T cells in children and adults with AD based on a systematic search. Currently, the clinical relevance and the pathomechanism of IgE autoantibodies in AD needs to be further investigated. Additionally, it is unknown whether the presence of IgE autoantibodies in patients with AD is an epiphenomenon or a disease endotype. However, increased knowledge on the clinical relevance and the pathophysiologic role of IgE autoantibodies and self-reactive T cells in AD can have consequences for diagnosis and treatment. Responses to the current available treatments can be used for better understanding of the pathways and may shed new lights on the treatment options for patients with AD and autoreactivity against skin epitopes. To conclude, IgE autoantibodies and self-reactive T cells can contribute to the pathophysiology of AD based on the body of evidence in literature. However, many questions remain open. Future studies on autoreactivity in AD should especially focus on the clinical relevance, the contribution to the disease progression and chronicity on cellular level, the onset and therapeutic strategies. [ABSTRACT FROM AUTHOR]

The restart of the meiotic cycle in Drosophila depends on both the controlled expression of Polo kinase and a protein called Matrimony (Mtrm), which binds to and physically inactivates Polo. [ABSTRACT FROM AUTHOR]

The pathogenesis of chronic inflammatory diseases is assumed to depend on activated T cells interacting with resident tissue cells or migratory inflammatory cells. The discovery of new T-cell subsets such as the IL-17–producing TH17 and T-regulatory cells innovated our understanding of T-cell biology. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets. The understanding of IL-17 and TH17 differentiation pathways has also changed the perspective of immunologists regarding the basis of chronic tissue inflammation, particularly where TH1 cells were considered as driving force of the pathology. This review summarizes the recent developments on TH cell subsets and integrates these findings into existing concepts of immunopathologic mechanisms. [Copyright &y& Elsevier]

Surfactant protein A (SP-A) and transforming growth factor-β1 (TGF-β1) have been shown to modulate the functions of different immune cells and specifically to inhibit T lymphocyte proliferation. The aim of the present study was to elucidate whether the Smad signaling pathway, which is activated by TOF-β1, also plays a role in SP-A-mediated inhibition of CD4+ T lymphocyte activation. Recombinant human SP-A1 expressed in Chinese hamster ovary cells [rSP-A1m (mammalian)], but not recombinant Baculovirus-derived rSP-A1hyp (hydroxyproline-deficient), suppressed T lymphocyte proliferation and IL-2 mRNA expression. To test whether SP-A induced Smad signaling, a Smad3/4-specific reporter gene was transfected in primary human CD4+ T lymphocytes. Only rSP-A1m, but not rSP-A1hyp, induced Smad-specific reporter genes, Srnad2 phosphorylation. and Smad7 mRNA expression. The effect of rSP-A1m was mediated through the TGF-βII and could be antagonized by anti-TGF-β1 neutralizing antibodies and sTGF-βRII. Western blot and ELISA analysis revealed that rSP-A1m, but not rSP-A1hyp, contained TGF-β1. TGFβ1 was responsible for the differences in inhibition of CD4β1 lymphocyte proliferation and activation of the Smad signaling pathway between rSP-A1hyp and rSP-A1hyp. After acidification, native SP-A. obtained from patients with alveolar proteinosis, also induced Smad signaling in human CD4+ T lymphocytes leading to an increased inhibition of T lymphocyte proliferation. thus indicating the presence of inactive, latent TGF-β1 in native SP-A samples. Association between SP-A and latent TGF-β1 provides a possible novel mechanism to regulate TGF-β1 -mediated inflammation and fibrosis reactions in the lung but also leads to possible misinterpretation of immune-modulator functions of SP-A. Monitoring of SP-A preparations for possible TGF-β1 is essential. [ABSTRACT FROM AUTHOR]

Background: Allergic asthma typically shows activated, allergen-specific CD4+ T cells in the early phase and airway remodeling in the late phase of the disease. Although TGF-β plays a crucial role in airway remodeling, it is only marginally induced in CD4+ T cells in the early allergen-dependent activation of the immune system. Objective: To elucidate the transition between early- and late-phase events, we investigated the role of activin A, a close family member of TGF-β. Methods: Activin A and TGF-β1 levels were measured systemically in the serum and in CD4+ T cells of asthmatic patients, as well as locally in the lung. Results: Activin A serum levels were increased in patients with severe asthma compared with levels in patients with moderate asthma and healthy control subjects, whereas all patients showed significantly increased TGF-β1 serum levels independent of disease severity. In T cells only patients with moderate asthma showed increased activin A mRNA expression, whereas TGF-β1 expression was equal to that seen in healthy subjects. Accordingly, ovalbumin sensitization in a mouse model of allergic asthma could induce activin A mRNA expression, but not TGF-β1 expression, in the lung. Immunohistochemistry of mice and human specimens revealed an abundant expression of activin A by infiltrating lymphocytes and structural cells of the lung. Although TGF-β1 more potently enhanced proliferation and Smad 2/3–dependent reporter genes in fibroblasts, activin A was capable of inducing TGF-β1 and vice versa. Conclusion: Activin A provides a link between acute allergen-specific T-cell responses and chronic TGF-β1–mediated airway remodeling in asthma. [Copyright &y& Elsevier]

Specific immunotherapy (SIT) represents the only curative treatment of allergy and is, therefore, of particular interest for immunological and pharmacological research. The current understanding of immunological mechanisms underlying SIT focuses on regulatory T cells (T regs), which balance Th1 and Th2 effector functions. This ensures that allergens are recognized, but tolerated by the immune system. There is clear evidence that SIT restores the disturbed balance of T regs and effector cells in allergic patients. Current efforts are focused to improve SIT regimens to make them more applicable in atopy and asthma. The current review provides an overview on the mechanisms of SIT and possible adjuvant treatment strategies on the background of the T reg concept. [ABSTRACT FROM AUTHOR]

Background: T cells are key regulators of immunologic disease parameters. However, their contribution to the process of tissue remodeling is ill defined. In the present study, we investigated gene expression of allergy-characteristic, IL-4-rich T cell cDNAs to monitor expression of genes that might participate in the pathogenesis of allergic diseases. Methods: cDNAs of freshly isolated and restimulated CD4+ T cells from patients with allergic asthma (AA) or atopic dermatitis (AD) and healthy subjects were analyzed on Nylon membrane-based DNA arrays. Three patients were selected for an allergy-characteristics T cell phenotype with high IL-4 expression (AA) or IL-13 expression (AD). Results: Several gene families such as the TGF-Β family, chemokines and chemokine receptors were found to be upregulated. Matrix metalloproteinases and their inhibitors were also found to be expressed in an enhanced manner. Furthermore, factors regulating tissue turnover such as fibroblast growth factors and neurotrophic as well as vasoactive factors were found be expressed at a higher level in allergic patient compared to healthy donors. Conclusion: The present study reveals and confirms genes relevant for allergy and highlights an approach to applying a DNA array technique for diagnostic discrimination of allergic diseases. [ABSTRACT FROM AUTHOR]

: The simultaneous occurrence of psoriasis driven by type 1 helper T (Th1) cells and type 17 helper T (Th17) cells and atopic eczema dominated by type 2 helper T (Th2) cells is rare. Here, we describe three patients with co-occurring psoriasis and atopic eczema with an antagonistic course and distinct T-cell infiltrates in lesions from psoriasis and those from atopic eczema. Sensitized patients with psoriasis had a reaction to epicutaneous allergen challenge, with clinically and histologically verified eczema lesions containing a large number of allergen-reactive T cells. These findings support a causative role for T cells triggered by specific antigens in both psoriasis and atopic eczema. (Supported by the German Research Foundation and others.) [ABSTRACT FROM PUBLISHER]

Abstract: FOXP3+CD4+ regulatory T cells (TR) have emerged as important regulators of immune responses. The aim of our study was to assess the frequency and functional characteristics of FOXP3+CD4+ TR in Crohn’s disease (CD). We report that FOXP3+CD4+ TR cells are expanded in mucosal lymphoid tissues (lamina propria and MLN) but are decreased in the PB in active CD. Patients treated with thiopurines, but not steroids or anti-TNF-α inhibitors, have a lower frequency of PB FOXP3+CD4+ TR (7.8±2.4% vs. 9.9±1.8%, p =0.01). FOXP3+ cells were localized in the lamina propria (LP), muscularis mucosa and serosa and accumulated in granulomas, whereas in MLN they localize in the T cell rich areas. MLN CD4+CD25+ T cells from both CD and normal intestine efficiently suppress the proliferation of effector CD4+CD25− T cells. T cell activation of MLN in vitro with anti-CD3 plus anti-CD28 Abs enhances the expression of FOXP3, both at the protein and transcriptional level, which is further enhanced by the addition of TGF-β. In summary, there is an expansion of FOXP3+CD4+ TR cells in mucosal lymphoid tissues in CD; they accumulate in areas of active inflammation, including granulomas and retain potent regulatory activity ex vivo. [Copyright &y& Elsevier]