Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling
Saeko NakajimaBotond Z. IgyártóTetsuya HondaGyohei EgawaAtsushi OtsukaMariko Hara‐ChikumaNorihiko WatanabeSteven F. ZieglerMichio TomuraKayo InabaYoshiki MiyachiDaniel H. KaplanKenji Kabashima
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Thymic stromal lymphopoietin
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.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.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.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.
Thymic stromal lymphopoietin
Allergic Inflammation
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Allergic inflammatory responses are believed to be inappropriate responses to innocuous environmental antigens that lead to chronic Th2-type responses. While the role of Th2 cytokines, especially IL-4 and IL-13, are well-documented in this response, the initial triggering factor remains to be determined. Our data suggests that the cytokine thymic stromal lymphopoietin (TSLP) is involved in both initiating and perpetuating allergic inflammatory responses. TSLP is expressed by epithelial cells at barrier surfaces, and its expression is elevated in the lesional skin of atopic dermatitis patients, and in the lungs of asthmatics. In the mouse, TSLP is elevated in antigen-driven models of airway inflammation, and transgenic expression in the skin or lung leads to the spontaneous development of inflammatory disease at the site of transgene expression. Finally, mice that cannot respond to TSLP fail to develop antigen-driven airway inflammation, showing that TSLP is both necessary and sufficient for this disease. We have used a variety of techniques to identify downstream mediators of TSLP-mediated disease, and show that dendritic cell responses to TSLP are critical to disease development. In addition, IL-4 and IL-13 are important mediators of TSLP signals, and functional blockade of these cytokines can reverse disease pathology. We have also extended the functional characterization of TSLP and disease to include contact hypersensitive responses to haptens, and have shown that antigens that require Th2-responses for disease development also require intact TSLP signaling, while those that use Th1-type cytokine responses do not. Taken as a whole, these data demonstrate the importance of TSLP to Th2-type immunity, and suggest that TSLP blockade may be an efficacious means of controlling allergic inflammatory responses. References
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The prevalence of allergic diseases such as allergic rhinitis is increasing, affecting up to 30% of the human population worldwide. Allergic sensitization arises from complex interactions between environmental exposures and genetic susceptibility, resulting in inflammatory T helper 2 (Th2) cell-derived immune responses towards environmental allergens. Emerging evidence now suggests that an epithelial dysfunction, coupled with inherent properties of environmental allergens, can be responsible for the inflammatory responses towards allergens. Several epithelial-derived cytokines, such as thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, influence tissue-resident dendritic cells (DCs) as well as Th2 effector cells. Exposure to environmental allergens does not elicit Th2 inflammatory responses or any clinical symptoms in nonatopic individuals, and recent findings suggest that a nondamaged, healthy epithelium lowers the DCs' ability to induce inflammatory T-cell responses towards allergens. The purpose of this review was to summarize the current knowledge on which signals from the airway epithelium, from first contact with inhaled allergens all the way to the ensuing Th2-cell responses, influence the pathology of allergic diseases.
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Even though thymic stromal lymphopoietin (TSLP) has been implicated in the development of allergic inflammation, its influence on immune tolerance mediated by regulatory T cells (Treg) have not been explored. We aimed to dissect the influence of TSLP on immunosuppressive activities of Treg and its potential consequences in human allergic asthma.In vitro culture system was utilized to study the effects of TSLP on human Treg. The functional competency of pulmonary Treg from a cohort of 15 allergic asthmatic, 15 healthy control, and 15 non-allergic asthmatic subjects was also evaluated by suppression assays and flow cytometric analysis.Activated pulmonary Treg expressed TSLP-R and responded to TSLP-mediated activation of STAT5. TSLP directly and selectively impaired IL-10 production of Treg and inhibited their suppressive activity. In human allergic asthma, pulmonary Treg exhibited a significant decrease in suppressive activity and IL-10 production compared to healthy control and non-allergic asthmatic counterparts. These functional alterations were associated with elevated TSLP expression in bronchoalveolar lavage fluid (BAL) of allergic asthmatic subjects. Furthermore, allergic asthmatic BAL could suppress IL-10 production by healthy control pulmonary Treg in a TSLP-dependent manner.These results provide the first evidences for a direct role of TSLP in the regulation of suppressive activities of Treg. TSLP mediated inhibition of Treg function might present a novel pathologic mechanism to dampen tolerogenic immune responses in inflamed asthmatic airway.
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Asthma is characterized by intense infiltration of eosinophils and CD4+ T cells into the submucosal tissue of airways. Accumulating evidence indicates that T helper type 2 cell-derived cytokines such as interleukin (IL)-4, IL-5 and IL-13 play critical roles in orchestrating and amplifying allergic inflammation in asthma. In addition, it has been suggested that newly identified cytokines including thymic stromal lymphopoietin, IL-25 and IL-33 are involved in the induction of allergic inflammation in asthma. In this review, we discuss the role of individual cytokines in the pathogenesis of asthma.
Thymic stromal lymphopoietin
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Pathogenesis
Proinflammatory cytokine
Interleukin 13
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Thymic stromal lymphopoietin(TSLP)is an interleukin 7-like cytokine that triggers dendritic cell-mediated T helper(Th)2 inflammatory responses.The pathogenic T cells involved in asthma are likely to be inflammatory Th2 cells.Mast cells also express TSLP receptor,TSLP greatly increases the production of selective Th2 cytokines.
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Thymic stromal lymphopoietin; Bronehial asthma; Inflammatory Th2 cells; Mast cells
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Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays an important role in the regulation of skin immunity and is upregulated in the lesions of atopic dermatitis patients. Therefore, inhibitors of TSLP production are effective as therapeutic agents for atopic dermatitis. In our laboratory, we found that hypoxia condition and DMOG, a PHD inhibitor, suppressed the expression of TSLP in keratinocytes. In this study, we analyzed the mechanism by which PHD inhibitors suppress TSLP expression.
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Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine and has been shown to be one of the factors released by epithelial cells following allergen contact with an important role instructing dendritic cells (DCs) to induce a T-helper type 2 (Th2) response. These TSLP-DC stimulate CD4(+) T cells to induce a proallergic cytokine profile, suggesting TSLP plays a crucial role in the initiation of the allergic cascade. Recently, evidence has also accumulated that TSLP could play a role in enhancement of the effector stages of the allergic response, with TSLP in synergy with IL-1 and tumor necrosis factor (TNF)-alpha shown to amplify cytokine secretion from mast cells. Also, the clinical relevance of TSLP has been demonstrated by both high levels of TSLP in skin biopsies from lesional atopic dermatitis patients and also increased expression of TSLP in asthmatic airway epithelial cells which correlated with reduced lung function. These studies suggest a critical role for TSLP as a driving factor in the emerging concept of tissue-specific control of immunity with TSLP secretion at the epithelial-DC interface acting as an initial factor in the proallergic cascade.
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CD4(+) Th2 cytokine responses promote the development of allergic inflammation and are critical for immunity to parasitic helminth infection. Recent studies highlighted that basophils can promote Th2 cytokine-mediated inflammation and that phenotypic and functional heterogeneity exists between classical IL-3-elicited basophils and thymic stromal lymphopoietin (TSLP)-elicited basophils. However, whether distinct basophil populations develop after helminth infection and their relative contributions to anti-helminth immune responses remain to be defined. After Trichinella spiralis infection of mice, we show that basophil responses are rapidly induced in multiple tissue compartments, including intestinal-draining lymph nodes. Trichinella-induced basophil responses were IL-3-IL-3R independent but critically dependent on TSLP-TSLPR interactions. Selective depletion of basophils after Trichinella infection impaired infection-induced CD4(+) Th2 cytokine responses, suggesting that TSLP-dependent basophils augment Th2 cytokine responses after helminth infection. The identification and functional classification of TSLP-dependent basophils in a helminth infection model, coupled with their recently described role in promoting atopic dermatitis, suggests that these cells may be a critical population in promoting Th2 cytokine-associated inflammation in a variety of inflammatory or infectious settings. Collectively, these data suggest that the TSLP-basophil pathway may represent a new target in the design of therapeutic intervention strategies to promote or limit Th2 cytokine-dependent immunity and inflammation.
Thymic stromal lymphopoietin
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Trichinella spiralis
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Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine expressed predominantly by barrier epithelial cells. TSLP is a potent activator of several cell types, including myeloid-derived dendritic cells, monocytes/macrophages and mast cells. Recent studies have revealed an important role for TSLP in the initiation and progression of allergic inflammatory diseases. In this review, we will discuss the role of TSLP in atopic diseases, as well as its function in immune homeostasis.
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