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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  TSLP and Immune Homeostasis 
In an immune system, dendritic cells (DCs) are professional antigen-presenting cells (APCs) as well as powerful sensors of danger signals. When DCs receive signals from infection and tissue stress, they immediately activate and instruct the initiation of appropriate immune responses to T cells. However, it has remained unclear how the tissue microenvironment in a steady state shapes the function of DCs. Recent many works on thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine that has the strong ability to activate DCs, provide evidence that TSLP mediates crosstalk between epithelial cells and DCs, involving in DC-mediated immune homeostasis. Here, we review recent progress made on how TSLP expressed within the thymus and peripheral lymphoid and non-lymphoid tissues regulates DC-mediated T-cell development in the thymus and T-cell homeostasis in the periphery.
doi:10.2332/allergolint.11-RAI-0394
PMCID: PMC3652583  PMID: 22270070
DC (Dendritic cell); homeostasis; regulatory T cell; thymus; TSLP
12.  Distinct Signal Codes Generate Dendritic Cell Functional Plasticity 
Science Signaling  2010;3(105):ra4.
Our adaptive immune system induces distinct responses to different pathogens because of the functional plasticity of dendritic cells (DCs); however, how DCs program unique responses remains unclear. Here, we found that the cytokine thymic stromal lymphopoietin (TSLP) potently transduced a unique T helper type 2 (TH2)–inducing compound signal in DCs. Whereas activation of nuclear factor κB (predominantly p50) drove DCs to produce OX40L to induce TH2 differentiation, the activation of signal transducer and activator of transcription 6 (STAT6) triggered DCs to secrete chemokines necessary for the recruitment of TH2 cells. In addition, TSLP signaling limited the activation of STAT4 and interferon regulatory factor 8 (IRF-8), which are essential factors for the production of the TH1-polarizing cytokine interleukin-12 (IL-12). By contrast, Toll-like receptor ligands and CD40 ligand did not activate STAT6 in myeloid DCs, but instead increased the abundance of STAT4 and IRF-8 to induce TH1 responses through the production of IL-12. Therefore, we propose that the functional plasticity of DCs relies on elaborate signal codes that are generated by different stimuli.
doi:10.1126/scisignal.2000567
PMCID: PMC3325779  PMID: 20086239
13.  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
14.  Thymic stromal lymphopoietin: a new cytokine in asthma 
Current opinion in pharmacology  2008;8(3):249-254.
Airway epithelial cells provide mechanical and immune protection against pathogens and allergens. Following activation, these cells produce a wide range of cytokines including thymic stromal lymphopoietin (TSLP). Recently it was established that a high level of TSLP is associated with asthma in mice and in humans. These findings suggest that interfering with the ability of cells to respond to TSLP might prevent the development of airway inflammation. Our review presents current knowledge on mediators that induce TSLP production and on the actions of TSLP on different populations of cells that are related to airway inflammation. TSLP affects dendritic cells, T cells, NKT cells, and mast cells, indicative of the broad role of TSLP in the regulation of inflammatory/allergic processes.
doi:10.1016/j.coph.2008.03.002
PMCID: PMC2518061  PMID: 18450510
15.  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
16.  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
17.  The T helper type 2 response to cysteine proteases requires dendritic cell–basophil cooperation via ROS-mediated signaling 
Nature immunology  2010;11(7):608-617.
The mechanisms that initiate T helper type 2 (TH2) responses are poorly understood. Here we demonstrate that cysteine protease–induced TH2 responses occur via ‘cooperation’ between migratory dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4). Subcutaneous immunization with papain plus antigen induced reactive oxygen species (ROS) in lymph node DCs and in dermal DCs and epithelial cells of the skin. ROS orchestrated TH2 responses by inducing oxidized lipids that triggered the induction of thymic stromal lymphopoietin (TSLP) by epithelial cells mediated by Toll-like receptor 4 (TLR4) and the adaptor protein TRIF; by suppressing production of the TH1-inducing molecules IL-12 and CD70 in lymph node DCs; and by inducing the DC-derived chemokine CCL7, which mediated recruitment of IL-4+ basophils to the lymph node. Thus, the TH2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.
doi:10.1038/ni.1883
PMCID: PMC3145206  PMID: 20495560
18.  TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling 
Thymic stromal lymphopoietin (TSLP) is a four-helix bundle cytokine that plays a critical role in the regulation of immune responses and in the differentiation of hematopoietic cells. TSLP signals through a heterodimeric receptor complex consisting of an interleukin-7 receptor α chain and a unique TSLP receptor (TSLPR) [also known as cytokine receptor-like factor 2 (CRLF2)]. Cellular targets of TSLP include dendritic cells, B cells, mast cells, regulatory T (Treg) cells and CD4+ and CD8+ T cells. The TSLP/TSLPR axis can activate multiple signaling transduction pathways including the JAK/STAT pathway and the PI-3 kinase pathway. Aberrant TSLP/TSLPR signaling has been associated with a variety of human diseases including asthma, atopic dermatitis, nasal polyposis, inflammatory bowel disease, eosinophilic eosophagitis and, most recently, acute lymphoblastic leukemia. A centralized resource of the TSLP signaling pathway cataloging signaling events is not yet available. In this study, we present a literature-annotated resource of reactions in the TSLP signaling pathway. This pathway map is publicly available through NetPath (http://www.netpath.org/), an open access signal transduction pathway resource developed previously by our group. This map includes 236 molecules and 252 reactions that are involved in TSLP/TSLPR signaling pathway. We expect that the TSLP signaling pathway map will provide a rich resource to study the biology of this important cytokine as well as to identify novel therapeutic targets for diseases associated with dysregulated TSLP/TSLPR signaling.
Database URL: http://www.netpath.org/pathways?path_id=NetPath_24
doi:10.1093/database/bau007
PMCID: PMC3935308  PMID: 24573880
19.  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
20.  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
21.  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
22.  Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells 
Compelling evidence suggests that the epithelial cell–derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell–mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell–mediated, TSLP-dependent activation of MCs may play a central role in “intrinsic” forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.
doi:10.1084/jem.20062211
PMCID: PMC2118732  PMID: 17242164
23.  Basophils induce Th2 immunity 
Virulence  2010;1(5):399-401.
Despite the fact that basophils represent less than 0.5% of circulating leukocytes, recent studies have begun to unveil their potent immunoregulatory functions, i.e., induction of Th2 immunity. It is believed that basophils are capable of doing so primarily by secreting key Th2-inducing cytokines, namely IL-4 and Thymic Stromal Lymphopoietin (TSLP), and by functioning as professional antigen presenting cells. However, we have recently demonstrated that Th2 immunity can develop in the absence of basophils or IL-4 during helminth infection. In this review, how basophils may (and may not) contribute to the development of Th2 immunity in vivo is discussed.
doi:10.4161/viru.1.5.12550
PMCID: PMC3073173  PMID: 21178477
basophils; CD4 T cells; IL-3; Nippostrongylus brasiliensis; Th2 immunity
24.  Thymic stromal lymphopoietin (TSLP) and allergic disease 
The importance of the epithelium in initiating and controlling immune responses is becoming more appreciated. For example, allergens contact first occurs at mucosal sites in exposed to the external environment such as the skin, airways and gastrointestinal tract. This exposure leads to the production of a variety of cytokines and chemokines that are involved in driving allergic inflammatory responses. One such product is thymic stromal lymphopoietin (TSLP). Recent studies, in both humans and mouse models, have implicated TSLP in the development and progression of allergic diseases. This review will highlight recent advances in the understanding of the role of TSLP in these inflammatory diseases. Importantly, these insights into TSLP's multifaceted roles could potentially allow for novel therapeutic manipulations of these disorders.
doi:10.1016/j.jaci.2012.07.010
PMCID: PMC3462264  PMID: 22939755
TSLP; asthma; allergy; atopic dermatitis; inflammation
25.  Allergen Recognition by Innate Immune Cells: Critical Role of Dendritic and Epithelial Cells 
Allergy is an exacerbated response of the immune system against non-self-proteins called allergens and is typically characterized by biased type-2 T helper cell and deleterious IgE mediated immune responses. The allergic cascade starts with the recognition of allergens by antigen presenting cells, mainly dendritic cells (DCs), leading to Th2 polarization, switching to IgE production by B cells, culminating in mast cell sensitization and triggering. DCs have been demonstrated to play a crucial role in orchestrating allergic diseases. Using different C-type lectin receptors DCs are able to recognize and internalize a number of allergens from diverse sources leading to sensitization. Furthermore, there is increasing evidence highlighting the role of epithelial cells in triggering and modulating immune responses to allergens. As well as providing a physical barrier, epithelial cells can interact with allergens and influence DCs behavior through the release of a number of Th2 promoting cytokines. In this review we will summarize current understanding of how allergens are recognized by DCs and epithelial cells and what are the consequences of such interaction in the context of allergic sensitization and downstream events leading to allergic inflammation. Better understanding of the molecular mechanisms of allergen recognition and associated signaling pathways could enable developing more effective therapeutic strategies that target the initial steps of allergic sensitization hence hindering development or progression of allergic diseases.
doi:10.3389/fimmu.2013.00356
PMCID: PMC3816228  PMID: 24204367
dendritic cell; epithelial cell; asthma; allergy; type-I hypersensitivity; house dust mite; pattern recognition receptor; TSLP

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