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1.  TSLP promotes IL-3-independent basophil hematopoiesis and type 2 inflammation 
Nature  2011;477(7363):229-233.
CD4+ T helper type 2 (Th2) cells characterized by their expression of IL-4, IL-5, IL-9 and IL-13 are required for immunity to helminth parasites1 and promote the pathological inflammation associated with asthma and allergic diseases2. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, suggesting that TSLP is a critical regulator of allergic diseases3-6. Supporting genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes Th2 cytokine-mediated immunity and inflammation5, 7-12. However, the mechanisms through which TSLP promotes Th2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses and that TSLPR-sufficient basophils can restore Th2 cell-dependent immunity in vivo. TSLP acted directly on bone marrow- resident progenitors to selectively promote basophil responses. Critically, TSLP could elicit basophil responses in both IL-3-sufficient and IL-3-deficient environments and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Further, activated human basophils expressed the TSLPR and basophils isolated from eosinophilic esophagitis (EoE) patients were heterogeneous. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil hematopoiesis and eliciting a population of functionally distinct basophils that promote Th2 cytokine-mediated inflammation.
doi:10.1038/nature10329
PMCID: PMC3263308  PMID: 21841801
TSLP; Th2 cytokine responses; innate immunity; basophils; hematopoiesis
2.  TSLP, OX40L, and IL-25 in Allergic Responses 
Summary
Allergic diseases are often triggered by environmental allergens that induce dominant type2 immune responses, characterized by the infiltrated TH2 lymphocytes, eosinophils, and elevated TH2 cytokines. In addition to TH2 type immune responses, epithelial stress and injury linked to tissue remodelling are often observed, suggesting that epithelial cells may play important role in regulating allergic responses. Dendritic cells (DCs), the professional antigen-presenting cells with the capabilities of sampling allergens, are considered as the key player on instructing TH2 immune responses. Whether inflamed epithelium can regulate innate immunity, such as macrophages and DCs, which in turns instruct adaptive immunity has long been hypothesized. Studies of TSLP (thymic stromal lymphopoietin), an epithelial cells-derived cytokine, that can strongly activate DCs, provide important evidences that the epithelial barrier can trigger allergic diseases by regulating immune responses. The finding that OX40/OX40L interactions are the molecular trigger responsible for the induction and maintenance of TH2 responses by TSLP-activated DCs provides a plausible molecular explanation for TSLP-mediated allergy. Recent progresses in characterizing the proinflammatory IL-17 cytokine family have added an additional layer of complexity on the regulation of allergic inflammation. TSLP-DCs can induce a robust expansion of TH2 memory cells and strengthen functional attributes by upregulating their surface expression of IL-17RB (IL-25R), the receptor for cytokine IL-17E (IL-25), a distinct member of IL-17 cytokine family. IL-17E (also know as IL-25) produced by epithelial cells, and other innate cells, such as eosinphils, basophils, and mast cells, are shown to regulate adaptive immunity by enhancing TH2 cytokine productions. These exciting findings expand our knowledge of the complex immunological cascades that result in allergic inflammation and may provide novel therapeutic approaches for the treatments of allergic diseases.
doi:10.1111/j.1365-2222.2009.03241.x
PMCID: PMC2744577  PMID: 19400908
3.  Signal transduction around thymic stromal lymphopoietin (TSLP) in atopic asthma 
Thymic stromal lymphopoietin (TSLP), a novel interleukin-7-like cytokine, triggers dendritic cell-mediated inflammatory responses ultimately executed by T helper cells of the Th2 subtype. TSLP emerged as a central player in the development of allergic symptoms, especially in the airways, and is a prime regulatory cytokine at the interface of virus- or antigen-exposed epithelial cells and dendritic cells (DCs). DCs activated by epithelium-derived TSLP can promote naïve CD4+ T cells to adopt a Th2 phenotype, which in turn recruite eosinophilic and basophilic granulocytes as well as mast cells into the airway mucosa. These different cells secrete inflammatory cytokines and chemokines operative in inducing an allergic inflammation and atopic asthma. TSLP is, thus, involved in the control of both an innate and an adaptive immune response. Since TSLP links contact of allergen with the airway epithelium to the onset and maintainance of the asthmatic syndrome, defining the signal transduction underlying TSLP expression and function is of profound interest for a better understandimg of the disease and for the development of new therapeutics.
doi:10.1186/1478-811X-6-5
PMCID: PMC2531181  PMID: 18724870
4.  Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells 
The continual rise of asthma in industrialised countries stands in strong contrast to the situation in developing lands. According to the modified Hygiene Hypothesis, helminths play a major role in suppressing bystander immune responses to allergens, and both epidemiological and experimental studies suggest that the tropical parasitic trematode Schistosoma mansoni elicits such effects. The focus of this study was to investigate which developmental stages of schistosome infection confer suppression of allergic airway inflammation (AAI) using ovalbumin (OVA) as a model allergen. Moreover, we assessed the functional role and localization of infection-induced CD4+Foxp3+ regulatory T cells (Treg) in mediating such suppressive effects. Therefore, AAI was elicited using OVA/adjuvant sensitizations with subsequent OVA aerosolic challenge and was induced during various stages of infection, as well as after successful anti-helminthic treatment with praziquantel. The role of Treg was determined by specifically depleting Treg in a genetically modified mouse model (DEREG) during schistosome infection. Alterations in AAI were determined by cell infiltration levels into the bronchial system, OVA-specific IgE and Th2 type responses, airway hyper-sensitivity and lung pathology. Our results demonstrate that schistosome infection leads to a suppression of OVA-induced AAI when mice are challenged during the patent phase of infection: production of eggs by fecund female worms. Moreover, this ameliorating effect does not persist after anti-helminthic treatment, and depletion of Treg reverts suppression, resulting in aggravated AAI responses. This is most likely due to a delayed reconstitution of Treg in infected-depleted animals which have strong ongoing immune responses. In summary, we conclude that schistosome-mediated suppression of AAI requires the presence of viable eggs and infection-driven Treg cells. These data provide evidence that helminth derived products could be incorporated into treatment strategies that specifically target suppression of immune responses in AAI by inducing Treg cells.
Author Summary
Infections with schistosomes, such as S. mansoni, S. japonicum and S. haematobium, are considered a major public health concern. Morbidity arises through granulomatous responses to eggs that become trapped in infected tissues. Interestingly, schistosomes belong to the group of helminths that have been shown to reduce allergy or autoimmunity. Indeed, the evidence provided by epidemiological surveys and experimental animal models has been so overwhelming that such helminths are now included in the Hygiene Hypothesis. However, since helminths provoke immunological responses that are similar to those seen in allergy (increased eosinophilia and IgE) it is suggested that additional mechanisms dampen such allergic responses. Helminth-induced regulatory T cells (Treg) are considered a component of these modulatory networks. Using an allergic airway inflammation model, we have elucidated that schistosome-mediated protection requires patency, that is, active egg production from fecund female worms. In addition, protection was shown to be mediated by infection-induced Treg. Interestingly, in endemic countries it is usually individuals with strong patent infections that show reduced allergic prevalence. Thus, further research into the immunomodulatory capacity of schistosome-egg derived factors may elucidate novel drug candidates or enhance treatment strategies to reduce allergic responses on the cellular level.
doi:10.1371/journal.pntd.0002379
PMCID: PMC3744427  PMID: 23967364
5.  Sensing the outside world: TSLP regulates barrier immunity 
Nature immunology  2010;11(4):289-293.
Thymic stromal lymphopoietin (TSLP) is an interleukin 7 (IL-7)-like cytokine originally characterized by its ability to promote the activation of B cells and dendritic cells (DCs). Subsequent studies have shown that TSLP promotes T helper type 2 (TH2) cell responses associated with immunity to some helminth parasites and the pathogenesis of many inflammatory diseases, including atopic dermatitis and asthma. This review will focus on recent findings indicating that in addition to influencing B cell and DC function, TSLP can promote TH2 cytokine–associated inflammation by directly promoting the effector functions of CD4+ TH2 cells, basophils and other granulocyte populations while simultaneously limiting the expression of DC-derived proinflammatory cytokines and promoting regulatory T cell responses in peripheral tissues.
doi:10.1038/ni.1852
PMCID: PMC2924817  PMID: 20300138
6.  Thymic Stromal Lymphopoietin Attenuates the Development of Atherosclerosis in ApoE−/− Mice 
Background
Thymic stromal lymphopoietin (TSLP) is a cytokine with multiple effects on the body. For one thing, TSLP induces Th2 immunoreaction and facilitates allergic reaction; for another, it promotes the differentiation of naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) and maintains immune tolerance. However, the exact role of TSLP in atherosclerosis remains unknown.
Methods and Results
In vitro, we examined the phenotype of TSLP‐conditioned bone marrow dendritic cells (TSLP‐DCs) of apolipoprotein E–deficient (ApoE−/−) mice and their capacity to induce the differentiation of Tregs. Our results indicated that TSLP‐DCs obtained the characteristics of tolerogenic dendritic cells and increased a generation of CD4+ latency‐associated peptide (LAP)+ Tregs and nTregs when cocultured with naive T cells. In addition, the functional relevance of TSLP and TSLP‐DCs in the development of atherosclerosis was also determined. Interestingly, we found that TSLP was almost absent in cardiovascular tissue of ApoE−/− mice, and TSLP administration increased the levels of antioxidized low‐density lipoprotein IgM and IgG1, but decreased the levels of IgG2a in plasma. Furthermore, mice treated with TSLP and TSLP‐DCs developed significantly fewer (32.6% and 28.2%, respectively) atherosclerotic plaques in the aortic root compared with controls, along with increased numbers of CD4+LAP+ Tregs and nTregs in the spleen and decreased inflammation in the aorta, which could be abrogated by anti‐TGF‐β antibody.
Conclusions
Our results revealed a protective role for TSLP in atherosclerosis that is possibly mediated by reestablishing a tolerogenic immune response, which may represent a novel possibility for treatment or prevention of atherosclerosis.
doi:10.1161/JAHA.113.000391
PMCID: PMC3835250  PMID: 23985377
atherosclerosis; CD4+LAP+ Tregs; TGF‐β; tolerogenic dendritic cells; TSLP
7.  Functions of Thymic Stromal Lymphopoietin in Immunity and Disease 
Immunologic Research  2012;52(3):211-223.
Thymic stromal lymphopoietin (TSLP) is an interleukin 7 (IL-7)-like cytokine expressed mainly by epithelial cells. Current studies provide compelling evidence that TSLP is capable of activating dendritic cells (DCs) to promote T helper (Th) 2 immune responses. TSLP has also been shown to directly promote Th2 differentiation of naïve CD4+ T cell, and activate natural killer T (NKT) cells, basophils and other innate immune cells at the initial stage of inflammation. In addition, TSLP affects B cell maturation and activation, and can also influence regulatory T (Treg) cell differentiation and development. TSLP-induced Th2 responses are associated with the pathogenesis of allergic inflammatory diseases, including atopic dermatitis (AD), asthma and rhinitis. Based on recent findings in humans and mouse models, TSLP might also be involved in the pathogenesis of inflammatory bowel disease and progression of cancer. In this review, we will summarize our current understanding of the biology of TSLP, and highlight the important issues for future investigations.
doi:10.1007/s12026-012-8264-z
PMCID: PMC3350568  PMID: 22274860
TSLP; allergy; Th2; cancer; inflammation
8.  Major histocompatibility complex class II-dependent basophil-CD4+ T cell interactions promote TH2 cytokine-dependent immunity 
Nature immunology  2009;10(7):697-705.
Dendritic cells can prime naïve CD4+ T cells, however we demonstrate that DC-mediated priming is insufficient for the development of TH2 cell-dependent immunity. We identify basophils as a dominant cell population that coexpressed MHC class II and Il4 message following helminth infection. Basophilia was promoted by thymic stromal lymphopoietin (TSLP) and depletion of basophils impaired immunity to helminth infection. In vitro, basophils promoted antigen-specific CD4+ T cell proliferation and IL-4 production and transfer of basophils augmented the expansion of helminth-responsive CD4+ T cells in vivo. Collectively, these studies suggest that MHC class II-dependent interactions between basophils and CD4+ T cells promote TH2 cytokine responses and immunity against helminth infection.
doi:10.1038/ni.1740
PMCID: PMC2711559  PMID: 19465906
Th2 cells; basophils; MHC class II; helminth infection
9.  On the hunt for helminths: Innate immune cells in the recognition and response to helminth parasites 
Cellular microbiology  2008;10(9):1757-1764.
The generation of protective immunity to helminth parasites is critically dependent upon the development of a CD4 T helper type 2 cytokine response. However, the host-parasite interactions responsible for initiating this response are poorly understood. This review will discuss recent advances in our understanding of how helminth-derived products are recognized by innate immune cells. Specifically, interactions between helminth excretory/secretory products and host Toll-like receptors and lectins will be discussed as well as the putative functions of helminth proteases and chitin in activating and recruiting innate immune cells. In addition, the functional significance of pattern recognition by epithelial cells, granulocytes, dendritic cells, and macrophages including expression of alarmins, thymic stromal lymphopoetin (TSLP), interleukin (IL)-25, IL-33, and Notch ligands in the development of adaptive anti-parasite Th2 cytokine responses and the future research challenges in this area will be examined.
doi:10.1111/j.1462-5822.2008.01174.x
PMCID: PMC2683372  PMID: 18505479
10.  OX40/OX40 Ligand Interactions in T-Cell Regulation and Asthma 
Chest  2012;141(2):494-499.
The OX40 receptor is preferentially expressed by T cells, and its cognate ligand OX40L is primarily expressed by antigen-presenting cells such as dendritic cells following activation by thymic stromal lymphopoietin (TSLP). TSLP is released by the bronchial epithelium, airway smooth muscle, and some inflammatory cells in response to numerous insults such as allergens, viruses, and physical damage. OX40L is a costimulatory molecule that plays a sentinel role in the adaptive immune response by promoting T helper (Th) 2 polarization of naive T cells within the lymph node. These polarized T cells produce Th2 cytokines such as IL-4, IL-5, and IL-13, which have been implicated particularly in allergic eosinophilic asthma. Animal models have positioned both TSLP and OX40/OX40L as critical in the development of airway inflammation and hyperreactivity. In human disease, there is good evidence that TSLP is upregulated in asthma, but there are limited data to demonstrate overexpression of OX40 or OX40L in disease. Targeting the OX40/OX40L axis or TSLP presents a novel therapeutic strategy that has the potential of modifying the disease process and, therefore, impacting on its natural history. Whether this approach can demonstrate efficacy in established disease rather than at disease onset is unknown. Biologic therapies directed toward OX40/OX40L are in early phases of development, and results from these studies are eagerly awaited.
doi:10.1378/chest.11-1730
PMCID: PMC3277294  PMID: 22315115
11.  Use of Humanised Rat Basophilic Leukaemia Cell Line RS-ATL8 for the Assessment of Allergenicity of Schistosoma mansoni Proteins 
Background
Parasite-specific IgE is thought to correlate with protection against Schistosoma mansoni infection or re-infection. Only a few molecular targets of the IgE response in S. mansoni infection have been characterised. A better insight into the basic mechanisms of anti-parasite immunity could be gained from a genome-wide characterisation of such S. mansoni allergens. This would have repercussions on our understanding of allergy and the development of safe and efficacious vaccinations against helminthic parasites.
Methodology/Principal Findings
A complete medium- to high-throughput amenable workflow, including important quality controls, is described, which enables the rapid translation of S. mansoni proteins using wheat germ lysate and subsequent assessment of potential allergenicity with a humanised Rat Basophilic Leukemia (RBL) reporter cell line. Cell-free translation is completed within 90 minutes, generating sufficient amounts of parasitic protein for rapid screening of allergenicity without any need for purification. Antigenic integrity is demonstrated using Western Blotting. After overnight incubation with infected individuals' serum, the RS-ATL8 reporter cell line is challenged with the complete wheat germ translation mixture and Luciferase activity measured, reporting cellular activation by the suspected allergen. The suitability of this system for characterization of novel S. mansoni allergens is demonstrated using well characterised plant and parasitic allergens such as Par j 2, SmTAL-1 and the IgE binding factor IPSE/alpha-1, expressed in wheat germ lysates and/or E. coli. SmTAL-1, but not SmTAL2 (used as a negative control), was able to activate the basophil reporter cell line.
Conclusion/Significance
This method offers an accessible way for assessment of potential allergenicity of anti-helminthic vaccine candidates and is suitable for medium- to high-throughput studies using infected individual sera. It is also suitable for the study of the basis of allergenicity of helminthic proteins.
Author Summary
Infection with parasitic helminths is characterised by a marked elevation of total and parasite-specific Immunoglobulin E (IgE). It is widely believed that this IgE response has evolved to protect hosts against large metazoan parasites. Such a protective function has been well characterised in particular against members of the genus Schistosoma. However, with a few notable exceptions, the molecular targets of the IgE response and the downstream immunological mechanisms leading to host protection are not well understood. The molecular targets of a specific IgE response are by definition called allergens. While almost 3,000 different allergens, contained in e.g. plant pollen or seeds, moulds or animal materials, have been characterised at the molecular level, and are listed and described in databases such as the Allergome database (www.allergome.org), only a few dozen allergens have been characterised in parasitic helminths. A more detailed understanding of the molecular targets of the anti-helminth IgE response can not only be expected to further our basic understanding of protective immune responses and allergy in general–such knowledge can also be expected to have important repercussions on the production of safe and effective anti-helminthic vaccines. This research describes a novel approach suitable for genome-wide functional identification of allergens in S. mansoni and other parasites, paving the way for the identification of the Schistosoma allergome.
doi:10.1371/journal.pntd.0003124
PMCID: PMC4177753  PMID: 25254513
12.  TSLP-dependent basophils promote TH2 cytokine responses following intestinal helminth infection1 
CD4+ T helper type 2 (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 versus TSLP-elicited basophils. However, whether distinct basophil populations develop following helminth infection, and their relative contributions to anti-helminth immune responses remain to be defined. Following 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 following Trichinella infection impaired infection-induced CD4+ TH2 cytokine responses, suggesting that TSLP-dependent basophils augment TH2 cytokine responses following 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 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.
doi:10.4049/jimmunol.1200691
PMCID: PMC3478488  PMID: 23024277
13.  TSLP-dependent basophils promote TH2 cytokine responses following intestinal helminth infection1 
CD4+ T helper type 2 (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 versus TSLP-elicited basophils. However, whether distinct basophil populations develop following helminth infection, and their relative contributions to anti-helminth immune responses remain to be defined. Following 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 following Trichinella infection impaired infection-induced CD4+ TH2 cytokine responses, suggesting that TSLP-dependent basophils augment TH2 cytokine responses following 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 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.
doi:10.4049/jimmunol.1200691
PMCID: PMC3478488  PMID: 23024277
14.  IL-25 elicits a multi-potent progenitor cell population that promotes Th2 cytokine responses 
Nature  2010;464(7293):1362-1366.
CD4pos T helper (Th) 2 cells secrete interleukin (IL)-4, IL-5 and IL-13 and are required for immunity to gastrointestinal helminth infections1. However, Th2 cells also promote chronic inflammation associated with asthma and allergic disorders2. The non-hematopoietic cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 (IL-17E) have been implicated in inducing Th2 cell-dependent inflammation at mucosal sites3-6, but how these cytokines influence innate immune responses remains poorly defined. Here we show that IL-25, a member of the IL-17 cytokine family, promotes the accumulation of a lineage negative (Linneg) multi-potent progenitor (MPP) cell population in the gut-associated lymphoid tissue (GALT) that promotes Th2 cytokine responses. The IL-25-elicited cell population, termed MPPtype2 cells, was defined by expression of Sca-1 and intermediate expression of c-kit (c-kitint) and exhibited multi-potent capacity, giving rise to cells of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. Progeny of MPPtype2 cells were competent antigen presenting cells and adoptive transfer of MPPtype2 cells could promote Th2 cytokine responses and confer protective immunity to helminth infection in normally susceptible Il17e-/- mice. The ability of IL-25 to induce the emergence of an MPPtype2 cell population identifies a link between the IL-17 cytokine family and extramedullary hematopoiesis and suggests a previously unrecognized innate immune pathway that promotes Th2 cytokine responses at mucosal sites.
doi:10.1038/nature08901
PMCID: PMC2861732  PMID: 20200520
IL-25 (IL-17E); Th2 cytokine responses; innate immunity; multi-potent progenitor; extramedullary hematopoiesis
15.  Embryonic Trophoblasts Induce Decidual Regulatory T Cell Differentiation and Maternal–Fetal Tolerance through Thymic Stromal Lymphopoietin Instructing Dendritic Cells 
Physiological pregnancy requires the maternal immune system to recognize and tolerate embryonic Ags. Although multiple mechanisms have been proposed, it is not yet clear how the fetus evades the maternal immune system. In this article, we demonstrate that trophoblast-derived thymic stromal lymphopoietin (TSLP) instructs decidual CD11c+ dendritic cells (dDCs)with increased costimulatory molecules; MHC class II; and Th2/3-type, but not Th1-type, cytokines. TSLP-activated dDCs induce proliferation and differentiation of decidual CD4+CD25− T cells into CD4+CD25+FOXP3+ regulatory T cells (Tregs) through TGF-β1. TSLP-activated dDC–induced Tregs display immunosuppressive features and express Th2-type cytokines. In addition, decidual CD4+CD25+FOXP3+ Tregs promote invasiveness and HLA-G expression of trophoblasts, resulting in preferential production of Th2 cytokines and reduced cytotoxicity in decidual CD56brightCD16− NK cells. Of interest, decreased TSLP expression and reduced numbers of Tregs were observed at the maternal–fetal interface during miscarriage. Our study identifies a novel feedback loop between embryo-derived trophoblasts and maternal decidual leukocytes, which induces a tolerogenic immune response to ensure a successful pregnancy.
doi:10.4049/jimmunol.1203425
PMCID: PMC3918863  PMID: 24453244
16.  A Critical Role for Thymic Stromal Lymphopoietin in Nickel-Induced Allergy in Mice 
Ni is the most frequent cause of contact allergy induced by metals. However, the underlying mechanism of this induction is unknown. Our previous research demonstrates that activation of dendritic cells (DCs) through p38MAPK/MKK6 is required for Ni-induced allergy in mice. In the current study, we investigated the cellular and molecular mechanisms underlying Ni-induced allergy using a mouse model that involves injecting Ni into the ear, with or without Freund’s incomplete or complete adjuvants. Nickel had greater potential to cause allergic reactions compared with palladium and gold. Among the proteins expressed at higher levels in mice with Ni-induced allergy, we focused on thymic stromal lymphopoietin (TSLP), which is produced in abundance by keratinocytes. We detected increased expression of the TSLP receptor (TSLPR) in DCs from cervical lymph nodes of mice with Ni-induced allergy, suggesting that DCs in ear tissues were activated through TSLPR signaling induced by keratinocyte-derived TSLP. Furthermore, delayed-type hypersensitivity reactions in mice with Ni-induced allergy were decreased significantly by injection of a Tslp–short interfering RNA along with atelocollagen in the ear skin. These results suggest that Ni allergy may be triggered by a TSLP/TSLPR-mediated interaction between epithelial and immune cells.
doi:10.4049/jimmunol.1300276
PMCID: PMC3993049  PMID: 24670797
17.  Thymic stromal lymphopoietin 
Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine expressed in skin, gut, lungs and thymus. TSLP signals via TSLPR, a heterodimer of the IL-7 receptor alpha chain (IL-7Rα) and the TSLP receptor chain (TSLPR), which is closely related to the common receptor-γ chain (γc), expressed on a wide range of cell types in the adptaive and innate immune system. TSLP exerts profound influence on the polarization of dendritic cells (DCs) to drive T helper (Th) 2 cytokine production. It also directly promotes T cell proliferation in response to T cell receptor (TCR) activation, and Th2 cytokine production. TSLP also supports B cell expansion and differentiation. TSLP further amplifies Th2 cytokine production by mast cells and NKT cells. These properties confer on TSLP a critical role in driving Th2 mediated inflammation. This role is supported by the finding that TSLP expression is up-regulated in keratinocytes of atopic dermatitis (AD) skin lesions and in bronchial epithelial cells in asthma.
doi:10.1111/j.1749-6632.2009.05128.x
PMCID: PMC2895428  PMID: 20146705
18.  IL-4 Derived from Non-T Cells Induces Basophil- and IL-3-independent Th2 Immune Responses 
Immune Network  2013;13(6):249-256.
How Th2 immunity develops in vivo remains obscure. Basophils have been considered key innate cells producing IL-4, a cytokine essential for Th2 immunity. Increasing evidence suggests that basophils are dispensable for the initiation of Th2 immunity. In this study, we revisited the role of basophils in Th2 immune responses induced by various types of adjuvants. Mice deficient in IL-3 or IL-3 receptor, in which basophil lymph node recruitment is completely abolished, fully developed wild type level Th2 CD4 T cell responses in response to parasite antigen or papain immunization. Similar finding was also observed in mice where basophils are inducibly ablated. Interestingly, IL-4-derived from non-T cells appeared to be critical for the generation of IL-4-producing CD4 T cells. Other Th2 promoting factors including IL-25 and thymic stromal lymphopoietin (TSLP) were dispensable. Therefore, our results suggest that IL-3- and basophil-independent in vivo Th2 immunity develops with the help of non-T cell-derived IL-4, offering an additional mechanism by which Th2 type immune responses arise in vivo.
doi:10.4110/in.2013.13.6.249
PMCID: PMC3875783  PMID: 24385943
Basophils; Papain; Parasites; Th2 immunity
19.  Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin–Conditioned Dendritic Cells Induce Regulatory T-Cell Differentiation and Protection of NOD Mice Against Diabetes 
Diabetes  2008;57(8):2107-2117.
OBJECTIVE—Autoimmune diabetes in the nonobese diabetic (NOD) mouse model results from a breakdown of T-cell tolerance caused by impaired tolerogenic dendritic cell development and regulatory T-cell (Treg) differentiation. Re-establishment of the Treg pool has been shown to confer T-cell tolerance and protection against diabetes. Here, we have investigated whether murine thymic stromal lymphopoietin (TSLP) re-established tolerogenic function of dendritic cells and induced differentiation and/or expansion of Tregs in NOD mice and protection against diabetes.
RESEARCH DESIGN AND METHODS—We examined the phenotype of TSLP-conditioned bone marrow dendritic cells (TSLP-DCs) of NOD mice and their functions to induce noninflammatory Th2 response and differentiation of Tregs. The functional relevance of TSLP and TSLP-DCs to development of diabetes was also tested.
RESULTS—Our results showed that bone marrow dendritic cells of NOD mice cultured in the presence of TSLP acquired signatures of tolerogenic dendritic cells, such as an absence of production of pro-inflammatory cytokines and a decreased expression of dendritic cell costimulatory molecules (CD80, CD86, and major histocompatibility complex class II) compared with LPS-treated dendritic cells. Furthermore, TSLP-DCs promoted noninflammatory Th2 response and induced the conversion of naïve T-cells into functional CD4+CD25+Foxp3+ Tregs. We further showed that subcutaneous injections of TSLP for 6 days or a single intravenous injection of TSLP-DCs protected NOD mice against diabetes.
CONCLUSIONS—Our study demonstrates that TSLP re-established a tolerogenic immune response in NOD mice and protects from diabetes, suggesting that TSLP may have a therapeutic potential for the treatment of type 1 diabetes.
doi:10.2337/db08-0171
PMCID: PMC2494678  PMID: 18477807
20.  Oesophagostomum dentatum Extract Modulates T Cell-Dependent Immune Responses to Bystander Antigens and Prevents the Development of Allergy in Mice 
PLoS ONE  2013;8(7):e67544.
One third of the human population is currently infected by one or more species of parasitic helminths. Certain helminths establish long-term chronic infections resulting in a modulation of the host’s immune system with attenuated responsiveness to “bystander” antigens such as allergens or vaccines. In this study we investigated whether parasite-derived products suppress the development of allergic inflammation in a mouse model. We show that extract derived from adult male Oesophagostomum dentatum (eMOD) induced Th2 and regulatory responses in BALB/c mice. Stimulation of bone marrow-derived dendritic cells induced production of regulatory cytokines IL-10 and TGF-beta. In a mouse model of birch pollen allergy, co-administration of eMOD with sensitizing allergen Bet v 1 markedly reduced the production of allergen-specific antibodies in serum as well as IgE-dependent basophil degranulation. Furthermore, eMOD prevented the development of airway inflammation, as demonstrated by attenuation of bronchoalveolar lavages eosinophil influx, peribronchial inflammatory infiltrate, and mucus secretion in lungs and IL-4 and IL-5 levels in lung cell cultures. Reduced secretion of Th2-related cytokines by birch pollen-re-stimulated splenocytes and mesenteric lymph node cells was observed in eMOD-treated/sensitized and challenged mice in comparison to sensitized and challenged controls. The suppressive effects of eMOD were heat-stable. Immunization with model antigens in the presence of eMOD reduced production of antibodies to thymus-dependent but not to thymus-independent antigen, suggesting that suppression of the immune responses by eMOD was mediated by interference with antigen presenting cell or T helper cell function but did not directly suppress B cell function. In conclusion, we have shown that eMOD possesses immunomodulatory properties and that heat-stable factors in eMOD are responsible for the dramatic suppression of allergic responses in a mouse model of type I allergy. The identification and characterization of parasite-derived immune-modulating molecules might have potential for designing novel prophylactic/therapeutic strategies for immune-mediated diseases.
doi:10.1371/journal.pone.0067544
PMCID: PMC3699627  PMID: 23844022
21.  PROTEASES INDUCE PRODUCTION OF THYMIC STROMAL LYMPHOPOIETIN BY AIRWAY EPITHELIAL CELLS THROUGH PROTEASE-ACTIVATED RECEPTOR-2i 
Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and triggers dendritic cell-mediated Th2-type inflammation. While TSLP is upregulated in epithelium of patients with asthma, the factors that control TSLP production have not been studied extensively. Because mouse models suggest roles for protease(s) in Th2-type immune responses, we hypothesized that proteases from airborne allergens may induce TSLP production in a human airway epithelial cell line, BEAS-2B. TSLP mRNA and protein were induced when BEAS-2B cells were exposed to prototypic proteases, namely trypsin and papain. TSLP induction by trypsin required intact protease activity and also a protease-sensing G protein-coupled receptor, protease-activated receptor (PAR)-2; TSLP induction by papain was partially dependent on PAR-2. In humans, exposure to ubiquitous airborne fungi, such as Alternaria, is implicated in the development and exacerbation of asthma. When BEAS-2B cells or normal human bronchial epithelial cells were exposed to Alternaria extract, TSLP was potently induced. The TSLP-inducing activity of Alternaria was partially blocked by treating the extract with a cysteine protease inhibitor, E64, or by infecting BEAS-2B cells with small interfering RNA for PAR-2. Protease-induced TSLP production by BEAS-2B cells was enhanced synergistically by IL-4 and abolished by IFN-γ. These findings demonstrate that TSLP expression is induced in airway epithelial cells by exposure to allergen-derived proteases and that PAR-2 is involved in the process. By promoting TSLP production in the airways, proteases associated with airborne allergens may facilitate the development and/or exacerbation of Th2-type airway inflammation, particularly in allergic individuals.
doi:10.4049/jimmunol.0900904
PMCID: PMC2706924  PMID: 19561109
Humans; cytokines; allergy; inflammation; lung
22.  Allergic sensitization: host-immune factors 
Allergic sensitization is the outcome of a complex interplay between the allergen and the host in a given environmental context. The first barrier encountered by an allergen on its way to sensitization is the mucosal epithelial layer. Allergic inflammatory diseases are accompanied by increased permeability of the epithelium, which is more susceptible to environmental triggers. Allergens and co-factors from the environment interact with innate immune receptors, such as Toll-like and protease-activated receptors on epithelial cells, stimulating them to produce cytokines that drive T-helper 2-like adaptive immunity in allergy-prone individuals. In this milieu, the next cells interacting with allergens are the dendritic cells lying just underneath the epithelium: plasmacytoid DCs, two types of conventional DCs (CD11b + and CD11b-), and monocyte-derived DCs. It is now becoming clear that CD11b+, cDCs, and moDCs are the inflammatory DCs that instruct naïve T cells to become Th2 cells. The simple paradigm of non-overlapping stable Th1 and Th2 subsets of T-helper cells is now rapidly being replaced by that of a more complex spectrum of different Th cells that together drive or control different aspects of allergic inflammation and display more plasticity in their cytokine profiles. At present, these include Th9, Th17, Th22, and Treg, in addition to Th1 and Th2. The spectrum of co-stimulatory signals coming from DCs determines which subset-characteristics will dominate. When IL-4 and/or IL-13 play a dominant role, B cells switch to IgE-production, a process that is more effective at young age. IgE-producing plasma cells have been shown to be long-lived, hiding in the bone-marrow or inflammatory tissues where they cannot easily be targeted by therapeutic intervention. Allergic sensitization is a complex interplay between the allergen in its environmental context and the tendency of the host’s innate and adaptive immune cells to be skewed towards allergic inflammation. These data and findings were presented at a 2012 international symposium in Prague organized by the Protein Allergenicity Technical Committee of the International Life Sciences Institute’s Health and Environmental Sciences Institute.
doi:10.1186/2045-7022-4-12
PMCID: PMC3989850  PMID: 24735802
Allergic sensitization; Protein; Allergic inflammation; Food allergy; Endogenous allergen
23.  TSLP promotes influenza-specific CD8+ T-cell responses by augmenting local inflammatory dendritic cell function 
Mucosal Immunology  2012;6(1):83-92.
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.
doi:10.1038/mi.2012.50
PMCID: PMC3534170  PMID: 22806096
24.  T Helper Cell Type 2 Cytokine–Mediated Comitogenic Responses and Ccr3 Expression during Differentiation of Human Mast Cells in Vitro 
Mast cells (MCs) arise in situ from circulating stem cell factor (SCF)-dependent committed progenitors (PrMCs) and accumulate at sites of allergic mucosal inflammation. We hypothesized that human (h)PrMCs and their mature counterparts might share overlapping patterns of chemokine and cytokine receptor utilization with eosinophils, basophils, and T helper type 2 (Th2) lymphocytes for their homing and allergy-associated hyperplasia. We have characterized committed hPrMCs and fully mature hMCs derived in vitro from cord blood for their functional responses to chemokine and cytokine agonists germane to allergic inflammation and for their maturation-related expression of the corresponding receptors. After 4 wk of culture in the presence of recombinant stem cell factor (SCF), interleukin (IL)-6, and IL-10, the cells were characterized as hPrMCs based upon their uniform surface expression of c-kit and CD13, low-level expression of Fc∈RIα, absence of CD14 and CD16 expression, and immunoreactivity for MC chymase in >80%, and about half were immunoreactive for tryptase and metachromatic with toluidine blue. By week 9, the cells had matured into hMCs, identified by higher levels of c-kit, continued expression of CD13 and low-level Fc∈RIα, uniform toluidine blue metachromasia, and uniform immunoreactivity for both tryptase and chymase. The 4-wk-old hPrMCs expressed four chemokine receptors (CXCR2, CCR3, CXCR4, and CCR5). Each receptor mediated transient rapid calcium fluxes in response to its respective ligand. Both recombinant human eotaxin and stromal cell–derived factor 1α elicited chemotaxis of hPrMCs. Only CCR3 was retained on the mature 9-wk-old hMCs from among these chemokine receptors, and hMCs responded to eotaxin with a sustained calcium flux but without chemotaxis. The Th2 cytokines IL-3, IL-5, IL-6, IL-9, and granulocyte/macrophage colony-stimulating factor each augmented the SCF-dependent proliferation of hPrMCs and hMCs. In contrast, the prototypical Th1 cytokine, interferon γ, suppressed SCF-driven proliferation of both hPrMCs and hMCs. Thus, throughout their development in vitro, hMCs obey SCF-dependent, cytokine-driven mitogenic responses that reflect a Th2-type polarization characteristic of allergy and asthma. Furthermore, committed hPrMCs have a unique profile of chemokine receptor expression from among reported hematopoietic cells, including CCR3, which is shared with the other cells central to allergic inflammation (eosinophils, basophils, and Th2 lymphocytes).
PMCID: PMC2195573  PMID: 10432289
chemokines; asthma; HIV; calcium flux; stem cell factor
25.  The Glycosylation Pattern of Common Allergens: The Recognition and Uptake of Der p 1 by Epithelial and Dendritic Cells Is Carbohydrate Dependent 
PLoS ONE  2012;7(3):e33929.
Allergens are initiators of both innate and adaptive immune responses. They are recognised at the site of entry by epithelial and dendritic cells (DCs), both of which activate innate inflammatory circuits that can collectively induce Th2 immune responses. In an attempt to have a better understanding of the role of carbohydrates in the recognition and uptake of allergens by the innate immune system, we defined common glycosylation patterns in major allergens. This was done using labelled lectins and showed that allergens like Der p 1 (Dermatophagoides pteronyssinus group 1), Fel d 1 (Felis domisticus), Ara h 1 (Arachis hypogaea), Der p 2 (Dermatophagoides pteronyssinus group 2), Bla g 2 (Blattella germanica) and Can f 1 (Canis familiaris) are glycosylated and that the main dominant sugars on these allergens are 1–2, 1–3 and 1–6 mannose. These observations are in line with recent reports implicating the mannose receptor (MR) in allergen recognition and uptake by DCs and suggesting a major link between glycosylation and allergen recognition. We then looked at TSLP (Thymic Stromal Lymphopoietin) cytokine secretion by lung epithelia upon encountering natural Der p 1 allergen. TSLP is suggested to drive DC maturation in support of allergic hypersensitivity reactions. Our data showed an increase in TSLP secretion by lung epithelia upon stimulation with natural Der p 1 which was carbohydrate dependent. The deglycosylated preparation of Der p 1 exhibited minimal uptake by DCs compared to the natural and hyperglycosylated recombinant counterparts, with the latter being taken up more readily than the other preparations. Collectively, our data indicate that carbohydrate moieties on allergens play a vital role in their recognition by innate immune cells, implicating them in downstream deleterious Th2 cell activation and IgE production.
doi:10.1371/journal.pone.0033929
PMCID: PMC3316510  PMID: 22479478

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