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1.  Thymic stromal lymphopoietin is induced by respiratory syncytial virus–infected airway epithelial cells and promotes a type 2 response to infection 
Background
Respiratory viral infection, including respiratory syncytial virus (RSV) and rhinovirus, has been linked to respiratory disease in pediatric patients, including severe acute bronchiolitis and asthma exacerbation.
Objective
The study examined the role of the epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) in the response to RSV infection.
Methods
Infection of human airway epithelial cells was used to examine TSLP induction after RSV infection. Air–liquid interface cultures from healthy children and children with asthma were also tested for TSLP production after infection. Finally, a mouse model was used to directly test the role of TSLP signaling in the response to RSV infection.
Results
Infection of airway epithelial cells with RSV led to the production of TSLP via activation of an innate signaling pathway that involved retinoic acid induced gene I, interferon promoter-stimulating factor 1, and nuclear factor-κB. Consistent with this observation, airway epithelial cells from asthmatic children a produced significantly greater levels of TSLP after RSV infection than cells from healthy children. In mouse models, RSV-induced TSLP expression was found to be critical for the development of immunopathology.
Conclusion
These findings suggest that RSV can use an innate antiviral signaling pathway to drive a potentially nonproductive immune response and has important implications for the role of TSLP in viral immune responses in general.
doi:10.1016/j.jaci.2012.07.031
PMCID: PMC4284103  PMID: 22981788
TSLP; RSV; asthma; epithelium; TH2
2.  Identification of the TSLP-Responsive dendritic cell subset critical for initiation of type-2 contact hypersensitivity 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(10):10.4049/jimmunol.1302175.
The cytokine thymic stromal lymphopoietin (TSLP) has been implicated in the initiation and progression of allergic inflammation through its ability to activate dendritic cells (DCs). However, the identity of the DC subset that responds to TSLP is not known. In this study we use a CCL17 reporter strain to identify the TSLP-responsive DC subset. In vitro, TSLP induced CD11bhigh DCs to express CCL17, to increase CCR7-mediated migration activity, and to drive Th2 differentiation of naïve CD4 T cells. In vivo, following skin sensitization, we found that a subset of antigen-bearing CCL17+ CD11bhigh migratory DCs (mDCs), but not antigen-bearing CCL17− mDCs, in skin LNs were capable of driving Th2 differentiation, and were dramatically reduced in TSLPR-deficient mice. Taken together, these results demonstrate that TSLP activated a subset of CD11b+ DCs in the skin to produce CCL17, upregulate CCR7 and migrate to the draining lymph node to initiate Th2 differentiation.
doi:10.4049/jimmunol.1302175
PMCID: PMC3826955  PMID: 24123684
TSLP; DC; CCL17; Th2
3.  The biology of thymic stromal lymphopoietin (TSLP) 
Originally shown to promote the growth and activation of B cells, thymic stromal lymphopoietin (TSLP) is now known to have wide-ranging impacts on both hematopoietic and non-hematopoietic cell lineages, including dendritic cells (DCs), basophils, eosinophils, mast cells, CD4+, CD8+ and natural killer (NK) T cells, B cells and epithelial cells. While TSLP's role in the promotion of TH2 responses has been extensively studied in the context of lung- and skin-specific allergic disorders, it is becoming increasingly clear that TSLP may impact multiple disease states within multiple organ systems, including the blockade of TH1/TH17 responses and the promotion of cancer and autoimmunity. This review will highlight recent advances in the understanding of TSLP signal transduction, as well as the role of TSLP in allergy, autoimmunity and cancer. Importantly, these insights into TSLP's multifaceted roles could potentially allow for novel therapeutic manipulations of these disorders.
doi:10.1016/B978-0-12-404717-4.00004-4
PMCID: PMC4169878  PMID: 23433457
allergy; atopy; cancer; cytokines; TSLP
4.  STAT5 is critical in Dendritic Cells for development of TH2- but not TH1-dependent Immunity 
Nature immunology  2013;14(4):364-371.
Dendritic cells (DCs) are a critical player in immune responses, linking innate and adaptive immunity. We show here that DC-specific deletion of the STAT5 was not critical for development, but was required for type-2, but not type-1, allergic responses in both the skin and lung. Loss of STAT5 in DCs led to the inability to respond to thymic stromal lymphopoietin (TSLP). STAT5 was required for TSLP-dependent DC activation, including upregulation of costimulatory molecules and chemokine production. Furthermore, type-2 responses in mice with DC-specific loss of STAT5resembled those seen in TSLPR-deficient mice. These results show that the TSLP- STAT5 axis in DCs is a critical component for the promotion of type-2 immunity at barrier surfaces.
doi:10.1038/ni.2541
PMCID: PMC4161284  PMID: 23435120
TSLP; Dendritic Cell; Contact Hypersensitivity; Stat5
5.  IL-33 and Thymic Stromal Lymphopoietin Mediate Immune Pathology in Response to Chronic Airborne Allergen Exposure 
Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. Here, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naïve mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria, and Aspergillus, for up to 8 weeks. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE antibody production, type 2 cytokine response and airway hyperreactivity (AHR) in 4 weeks, followed by airway remodeling in 8 weeks. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells (ILC2s) was observed. CD4+ T cells and ILC2s contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33 receptor (Il1rl1−/−) and TSLP receptor (Tslpr−/−) showed significant reduction in airway inflammation, IgE antibody levels and AHR. In contrast, mice deficient in IL-25 receptor or IL-1 receptor showed minimal differences as compared to wild-type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and TSLP likely play key roles in this process.
doi:10.4049/jimmunol.1302984
PMCID: PMC4119518  PMID: 25015831
6.  IL-33 and Thymic Stromal Lymphopoietin Mediate Immune Pathology in Response to Chronic Airborne Allergen Exposure 
Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. Here, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naïve mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria, and Aspergillus, for up to 8 weeks. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE antibody production, type 2 cytokine response and airway hyperreactivity (AHR) in 4 weeks, followed by airway remodeling in 8 weeks. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells (ILC2s) was observed. CD4+ T cells and ILC2s contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33 receptor (Il1rl1−/−) and TSLP receptor (Tslpr−/−) showed significant reduction in airway inflammation, IgE antibody levels and AHR. In contrast, mice deficient in IL-25 receptor or IL-1 receptor showed minimal differences as compared to wild-type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and TSLP likely play key roles in this process.
doi:10.4049/jimmunol.1302984
PMCID: PMC4119518  PMID: 25015831
7.  Allergen-specific CD4 T cells respond indirectly to TSLP to promote allergic responses in the skin 
TSLP is an epithelial-derived cytokine that has been implicated in the initiation of allergic responses. CD4 T cells and dendritic cells are able to respond to TSLP in vitro; however, there has not been a careful dissection of the spatiotemporal response to TSLP by CD4 T cells in vivo during an allergic response. Previous work has suggested a requirement for TSLP in amplifying Th2 responses during allergen challenge by direct action on CD4 T cells, however these studies did not determine whether there is an effect of TSLP on CD4 T cells during allergen sensitization. Here we demonstrate an indirect role for TSLP on CD4 T cells during sensitization and challenge phases of an allergic response. This indirect effect of TSLP on CD4 T cells is due in part to the presence of TSLP exclusively in the allergen sensitized and challenged skin, rather than the draining lymph nodes.
doi:10.4049/jimmunol.1201677
PMCID: PMC3657711  PMID: 23543759
TSLP; allergen; sensitization; challenge; CD4 T cell
8.  TSLP Amplifies the Differentiation of Alternatively Activated Macrophages1 
The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) has been associated with the promotion of type 2 inflammation and the induction of allergic disease. In humans TSLP is elevated in the lungs of asthma patients and in the lesional skin of individuals with atopic dermatitis, while mice lacking TSLP responses are refractory to models of Th2-driven allergic disease. While several cell types, including dendritic cells, basophils, and CD4 T cells, have been shown to respond to TSLP, its role in macrophage differentiation has not been studied. Type 2 cytokines (i.e. IL-4 and IL-13) can drive the differentiation of macrophages into alternatively activated macrophages (aaMΦ, also referred to as M2 macrophages). This population of macrophages is associated with allergic inflammation. We therefore reasoned that TSLP/TSLPR signaling may be involved in the differentiation and activation of aaMΦs during allergic airway inflammation. We report here that TSLP changes the quiescent phenotype of pulmonary macrophages toward an aaMΦ phenotype during TSLP-induced airway inflammation. This differentiation of airway macrophages was IL-13-, but not IL-4-, dependent. Taken together, we demonstrate here that TSLP/TSLPR plays a significant role in the amplification of aaMΦ polarization and chemokine production, thereby contributing to allergic inflammation.
doi:10.4049/jimmunol.1201808
PMCID: PMC3549221  PMID: 23275605
TSLP; asthma; alternatively activated macrophages
9.  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
10.  A Novel, Human-Specific Interacting Protein Couples FOXP3 to a Chromatin Remodeling Complex that Contains KAP1/TRIM28 
Regulatory T cells (Treg) play a pivotal role for the maintenance of immunological self-tolerance. Deficiency or dysfunction of Treg leads to severe autoimmune diseases. While the forkhead/winged-helix family member FOXP3 is critical for Treg differentiation and function, the molecular basis for FOXP3 function remains unclear. Here we identified and characterized a human-specific FOXP3 interacting protein, referred to as FIK (FOXP3-Interacting KRAB-domain containing protein). FIK is highly expressed in Tregs and acts as a bridging molecule to link FOXP3 with the chromatin remodeling scaffold protein KAP1 (TIF-1β/TRIM28). Disruption of the FOXP3-FIK-KAP1 complex in Tregs restored expression of FOXP3-target genes and abrogated the suppressor activity of the Tregs. These data demonstrate a critical role for FIK in regulating FOXP3 activity and Treg function.
doi:10.4049/jimmunol.1203561
PMCID: PMC4197931  PMID: 23543754
11.  Resident renal mononuclear phagocytes comprise five discrete populations with distinct phenotypes and functions 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(6):10.4049/jimmunol.1300342.
Recent reports have highlighted greater complexity, plasticity and functional diversity of mononuclear phagocytes (MPCs), including monocytes, macrophages and dendritic cells (DCs), in our organs, than previously understood. The functions and origins of MPCs resident within healthy organs, especially in the kidney, are less well understood, while studies suggest they play roles in disease states distinct from recruited monocytes. We developed an unbiased approach using flow cytometry to analyze MPCs residing in the normal mouse kidney, and identified five discrete subpopulations according to CD11b/CD11c expression as well as F4/80, CD103, CD14, CD16 and CD64 expression. In addition to distinct marker profiles, these subpopulations have different lineages and expression of genes involved in tissue homeostasis, including angiogenesis. Among them, the CD11bint CD11cint F4/80hi subpopulation notably exhibited high capacity to produce a representative anti-inflammatory cytokine, IL-10. Each subpopulation had different degrees of both macrophage (phagocytosis) and DC (antigen presentation) capacities, with a tendency to promote differentiation of regulatory T cells, while two of these showed expression of transcription factors reported to be highly expressed by classical DCs, and proclivity to exit the kidney following stimulation with LPS. In summary, resident kidney MPCs comprise discrete subpopulations, which cannot be simply classified into the conventional entities, and they produce anti-inflammatory and tissue-homeostatic factors to differing degrees.
doi:10.4049/jimmunol.1300342
PMCID: PMC3808972  PMID: 23956422
12.  Respiratory syncytial virus induces functional thymic stromal lymphopoietin receptor in airway epithelial cells 
The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) plays a key role in the development and progression of atopic disease and has notably been shown to directly promote the allergic inflammatory responses that characterize asthma. Current models suggest that TSLP is produced by epithelial cells in response to inflammatory stimuli and acts primarily upon dendritic cells to effect a T helper type 2-type inflammatory response. Recent reports, however, have shown that epithelial cells themselves are capable of expressing the TSLP receptor (TSLPR), and may thus directly contribute to a TSLP-dependent response. We report here that beyond simply expressing the receptor, epithelial cells are capable of dynamically regulating TSLPR in response to the same inflammatory cues that drive the production of TSLP, and that epithelial cells produce chemokine C–C motif ligand 17, a T helper type 2-associated chemokine, in response to stimulation with TSLP. These data suggest that a direct autocrine or paracrine response to TSLP by epithelial cells may initiate the initial waves of chemotaxis during an allergic inflammatory response. Intriguingly, we find that the regulation of TSLPR, unlike TSLP, is independent of nuclear factor kappa-light-chain-enhancer of activated B cells, suggesting that the cell may be able to independently regulate TSLP and TSLPR levels in order to properly modulate its response to TSLP. Finally, we show evidence for this dynamic regulation occurring following the viral infection of primary epithelial cells from asthmatic patients. Taken together, the data suggest that induction of TSLPR and a direct response to TSLP by epithelial cells may play a novel role in the development of allergic inflammation.
doi:10.2147/JIR.S42381
PMCID: PMC3617816  PMID: 23576878
TSLP; TSLPR; RSV; asthma; epithelium
13.  Thymic Stromal Lymphopoietin Amplifies the Differentiation of Alternatively Activated Macrophages 
The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) has been associated with the promotion of type 2 inflammation and the induction of allergic disease. In humans TSLP is elevated in the lungs of asthma patients and in the lesional skin of individuals with atopic dermatitis, whereas mice lacking TSLP responses are refractory to models of Th2-driven allergic disease. Although several cell types, including dendritic cells, basophils, and CD4 T cells, have been shown to respond to TSLP, its role in macrophage differentiation has not been studied. Type 2 cytokines (i.e., IL-4 and IL-13) can drive the differentiation of macrophages into alternatively activated macrophages (aaMϕs, also referred to as M2 macrophages). This population of macrophages is associated with allergic inflammation. We therefore reasoned that TSLP/TSLPR signaling may be involved in the differentiation and activation of aaMϕs during allergic airway inflammation. In this study, we report that TSLP changes the quiescent phenotype of pulmonary macrophages toward an aaMϕ phenotype during TSLP-induced airway inflammation. This differentiation of airway macrophages was IL-13–, but not IL-4–, dependent. Taken together, we demonstrate in this study that TSLP/TSLPR plays a significant role in the amplification of aaMΦ polarization and chemokine production, thereby contributing to allergic inflammation.
doi:10.4049/jimmunol.1201808
PMCID: PMC3549221  PMID: 23275605
14.  Thymic stromal lymphopoietin (TSLP)-mediated dermal inflammation aggravates experimental asthma 
Mucosal immunology  2012;5(3):342-351.
Individuals with one atopic disease are far more likely to develop a second. Approximately half of all atopic dermatitis (AD) patients subsequently develop asthma, particularly those with severe AD. This association, suggesting a role for AD as an entry point for subsequent allergic disease, is a phenomenon known as the ‘atopic march’. While the underlying cause of the atopic march remains unknown, recent evidence suggests a role for the cytokine TSLP. We have established a mouse model to determine whether TSLP plays a role in this phenomenon, and in this study show that mice exposed to the antigen OVA in the skin in the presence of TSLP develop severe airway inflammation when later challenged with the same antigen in the lung. Interestingly, neither TSLP production in the lung nor circulating TSLP is required to aggravate the asthma that was induced upon subsequent antigen challenge. However, CD4 T cells are required in the challenge phase of the response, as was challenge with the sensitizing antigen, demonstrating that the response was antigen-specific. This study, which provides a clean mouse model to study human atopic march, indicates that skin-derived TSLP may represent an important factor that triggers progression from atopic dermatitis to asthma.
doi:10.1038/mi.2012.14
PMCID: PMC3328620  PMID: 22354320
TSLP; atopic dermatitis; atopic march; mouse model
15.  TSLP enhances the function of helper type2 cells* 
European journal of immunology  2011;41(7):1862-1871.
The cytokine thymic stromal lymphopoietin (TSLP) has been implicated in the development and progression of allergic inflammation in both humans and mice. TSLP has been shown to promote Th2-type response through upregulation of OX40L on dendritic cells, and through direct induction of IL-4 production in naïve CD4 T cells. However, its direct effect on effector Th cells has not been extensively investigated. In this study, we show that the level of TSLPR expression on mouse effector Th2 cells is higher than on Th1 and Th17 cells, and that TSLP induced proliferation of effector Th2, but not Th1 and Th17 cells. TSLP also induced the phosphorylation of Signal Transducer and Activator of Transcription (Stat) 5, and expression of anti-apoptotic factor Bcl-2 in Th2 cells. Finally, TSLP-mediated proliferation on Th2 cells was enhanced by TCR stimulation, through IL-4-mediated induction of TSLPR expression. Taken together, these results indicate that TSLP is involved in exacerbation of mouse Th2-mediated allergic inflammation in a Th2 environment through direct stimulation of Th2 effector cells.
doi:10.1002/eji.201041195
PMCID: PMC3124605  PMID: 21484783
TSLPR; TSLP; Th2 cell; IL-4
16.  Hepatitis C virus promotes Th17 responses through TSLP production by infected hepatocytes 
Hepatology (Baltimore, Md.)  2013;57(4):1314-1324.
Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Here, we report that infection of hepatic cells by HCV stimulates NFκB-dependent production of thymic stromal lymphopoietin (TSLP). Hepatocyte-derived TSLP in turn conditions DCs to drive Th17 differentiation. The TSLP secreted by HCV-infected hepatoma cells is capable of activating human monocyte-derived DCs by upregulating the expression of CD40, CD86, CCL17, CCL22, and CCL20 which is activating marker of DCs. In addition, the production of key cytokines for Th17 differentiation, TGF-β, IL-6 and IL-21, is enhanced by human monocytes upon co-culture with HCV-infected cells. Importantly, the blockade of TSLP using neutralizing antibody prevented the activation and maturation of DCs as well as the production of Th17 differentiation cytokines. DCs conditioning by TSLP secreted from HCV-infected cells activated naïve CD4+ T lymphocytes, resulting in Th17 differentiation. Furthermore, we can detect substantial levels of hepatocyte TSLP in fibrotic liver tissue from chronic HCV patients. Thus, blockade of TSLP released by HCV-infected hepatocytes may suppress the induction/maintenance of hepatic Th17 responses and halt the progression of chronic liver disease to fibrosis and liver failure.
Conclusion
Hepatocyte-derived TSLP conditions DCs to drive Th17 differentiation. Treatment of TSLP neutralizing antibody in HCV-infected hepatocyte/DC coculture abrogates DC conditioning and thereby inhibits Th17 differentiation.
doi:10.1002/hep.26128
PMCID: PMC3582737  PMID: 23150092
17.  TSLP conditions the lung immune environment for the generation of pathogenic innate and antigen-specific adaptive immune responses1 
Thymic Stromal Lymphopoietin (TSLP) is crucial for the development of atopic diseases in humans and mice. Mice that express a lung-specific TSLP transgene (SPC-TSLP) develop a spontaneous and progressive asthma-like disease, suggesting that TSLP expression alone was sufficient for disease development. Here we show that, in fact, TSLP alone only causes a weak innate response that is insufficient for development of full airway inflammatory disease. Complete disease development requires both TSLP and antigenic stimulation. These data suggest that the spontaneous lung inflammation observed in SPC-TSLP mice reflects a TSLP-driven predisposition towards the development of aberrant responses against innocuous environmental antigens. This provides evidence that TSLP may act directly to induce susceptibility to the inappropriate allergic responses that characterize atopy and asthma. We additionally show that disease development requires CD4 T cells but not B cells. Further, we reveal a TSLP-driven innate response involving mucus overproduction and goblet cell metaplasia. Taken together, these data suggest a multi-faceted model of TSLP-mediated airway inflammation, with an initial activation of resident innate immune cells, followed by activation of the adaptive immune system and full disease development. This study provides new insight into the unique features of the asthma pathology contributed by the innate and adaptive immune responses in response to TSLP stimulation.
PMCID: PMC3195412  PMID: 19155513
Cytokines; Allergy; Inflammation; Lung
18.  De Novo Induction of Functional Foxp3+ Regulatory CD4 T Cells in Response to Tissue-Restricted Self Antigen 
Naïve CD4 T cells can differentiate into a number of functional subsets in response to antigen, including Foxp3+ induced regulatory T cells (iTreg). The in vivo development and function of iTreg has been primarily demonstrated in systems involving antigen encountered systemically or delivered via the intestinal mucosa. In this study, we demonstrate that de novo Foxp3 expression in naïve CD4 T cells is a critical mechanism for establishing tolerance for a tissue-restricted neo-self antigen. Naïve CD4 T cells lacking a functional Foxp3 gene cannot achieve tolerance, but can be suppressed in vivo in the presence of wild-type naïve CD4 T cells. Exposure to non-specific inflammation during priming undermines tolerance through impaired Foxp3 induction, suggesting that the microenvironment also plays a role. Together, these data show that de novo Foxp3 expression is an integral component of establishment and maintenance of tolerance among naïve peripheral CD4 T cells.
doi:10.4049/jimmunol.1003573
PMCID: PMC3195414  PMID: 21402894
19.  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
20.  Dibutyl Phthalate (DBP) Induced Thymic Stromal Lymphopoietin (TSLP) Is Required for Th2 Contact Hypersensitivity Responses1 
Thymic stromal lymphopoietin (TSLP) is an IL-7 related cytokine, produced by epithelial cells, that has been linked to atopic dermatitis and asthma; however, it remains unclear how TSLP shapes the adaptive immune response that causes these allergic disorders. Here we demonstrate a role for TSLP in a Th2 model of contact hypersensitivity (CHS) in mice. TSLP is required for the development of Th2-type CHS induced by the hapten fluorescein isothiocyanate (FITC) in combination with the sensitizing agent dibutyl phthalate (DBP). TSLPR−/− mice exhibited a dramatically reduced response, including markedly reduced local infiltration by eosinophils, Th2 cytokine production, and serum IgE levels, following FITC sensitization and challenge. The reduced response by TSLPR−/− mice is likely due to decreased frequency, and reduced T cell stimulatory function, of skin-derived antigen-bearing FITC+CD11c+ dendritic cells (DCs) in draining lymph nodes following FITC sensitization. These data suggest that skin-derived DCs are direct or indirect targets of TSLP in the development of type-2 immune responses in the skin, where TSLP drives their maturation, accumulation in skin draining lymph nodes, and ability to induce proliferation of naïve allergen-specific T cells.
doi:10.4049/jimmunol.0803478
PMCID: PMC2922850  PMID: 20173025
Th1/Th2 Cells; Inflammation; Allergy; Dendritic Cells; Rodent
21.  Inhibition of NFκB-Mediated TSLP Expression by Retinoid X Receptor 
The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) has important roles in the initiation of allergic airway inflammation and activation of dendritic cells. We have shown that the human TSLP gene is regulated in an NFκB-dependent manner; however the factors that negatively regulate TSLP expression are not known. In this paper we demonstrate that 9-cis retinoic acid (9-cisRA) is a negative regulator of TSLP expression in airway epithelial cells. This inhibition is manifested as a block in the IL-1β-mediated recruitment of NFκB to the human TSLP promoter. 9-cisRA-mediated inhibition is not restricted to TSLP gene expression, but rather reflected a general inhibition of NFκB activation as other NFκB-regulated-genes were also inhibited in a similar manner by 9-cisRA treatment. Taken as a whole, these data demonstrate that inhibition of IL-1β-dependent genes by active RXR involves antagonism of NFκB signaling.
PMCID: PMC2878481  PMID: 18832669
22.  FOXP3 and the Regulation of Treg/Th17 Differentiation 
CD4 T cell lineages are marked by the signature transcription factor each lineage expresses. For example, regulatory T cells (Tregs) are characterized by expression of FOXP3, which is either induced during thymic development for natural Tregs (nTregs), or in the periphery in the presence of TGFβ and retinoic acid for induced Tregs (iTreg). Interestingly, recent work has shown that the signature transcription factor for Th17 cells, RORγt, is also induced by TGFβ, thus linking the differentiation of the Treg and Th17 lineages. In the absence of a second signal from a proinflammatory cytokine, FOXP3 can inhibit RORγt function and drive Treg differentiation. However, when the cell also receives a signal from a proinflammation cytokine (e.g., IL-6), FOXP3 function is inhibited and the Th17 differentiation pathway is induced. Therefore, it is the balance between FOXP3 and RORγt function that determines CD4 T cell fate and the type of immune response that will be generated.
doi:10.1016/j.micinf.2009.04.002
PMCID: PMC2728495  PMID: 19371792
FOXP3; Regulatory T Cell; Th17
23.  Paradoxically Increased FOXP3+ T Cells in IBD Do Not Preferentially Express the Isoform of FOXP3 Lacking Exon 2 
Digestive diseases and sciences  2012;57(11):2846-2855.
Background
FOXP3+ regulatory T cells (Tregs) are critical for controlling inflammation in the gastrointestinal (GI) tract. There is a paradoxical increase of mucosal FOXP3+ T cells in patients with inflammatory bowel disease (IBD). These FOXP3+ cells were recently shown to include IL-17A-producing cells in Crohn’s disease, resembling Th17 cells implicated in autoimmune diseases. FOXP3 inhibits IL-17A production, but a naturally-occurring splice variant of FOXP3 lacking exon 2 (Δexon2) cannot.
Aims
We hypothesized that IBD patients preferentially express the Δexon2 variant of FOXP3 so the paradoxically increased mucosal Tregs in IBD could represent cells expressing only Δexon2.
Methods
We used antibodies and primers that can distinguish between the full-length and Δexon2 splice variant of FOXP3 to evaluate expression of these isoforms in human intestinal tissue by immunohistochemistry (IHC) and quantitative PCR, respectively.
Results
No difference in the expression pattern of Δexon2 relative to full length FOXP3 was seen in ulcerative colitis (UC) or Crohn’s disease versus non-IBD controls. By immunofluorescence microscopy and flow cytometry, we also did not find individual cells which expressed FOXP3 protein exclusively in the Δexon2 isoform in either IBD or control tissue. FOXP3+ mucosal CD4+ T cells from both IBD and control specimens were able to make IL-17A in vitro after PMA and ionomycin stimulation, but these cells did not preferentially express Δexon2.
Conclusions
Our data do not support the hypothesis that selective expression of FOXP3 in the Δexon2 isoform accounts for the inability of copious FOXP3+ T cells to inhibit inflammation or IL-17 expression in IBD.
doi:10.1007/s10620-012-2292-3
PMCID: PMC3482978  PMID: 22736020
FOXP3; Interleukin-17A; Th17; Treg
24.  Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand 
Background
Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in TH2 priming and polarization.
Objectives
We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection.
Methods
Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12.
Results
OX40L was expressed mainly on CD11c+MHC class II (MHCII)+CD11b+ DCs but not CD103+ DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection.
Conclusions
In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and TH2 polarization, accounting for the enhanced response on reinfection.
doi:10.1016/j.jaci.2012.08.033
PMCID: PMC3593657  PMID: 23036746
Respiratory syncytial virus; OX40 ligand; thymic stromal lymphopoietin
25.  Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin 
The cytokine thymic stromal lymphopoietin (TSLP) has recently been implicated in the pathogenesis of atopic dermatitis (AD) and other allergic diseases in humans. To further characterize its role in this disease process, transgenic mice were generated that express a keratinocyte-specific, tetracycline-inducible TSLP transgene. Skin-specific overexpression of TSLP resulted in an AD-like phenotype, with the development of eczematous lesions containing inflammatory dermal cellular infiltrates, a dramatic increase in Th2 CD4+ T cells expressing cutaneous homing receptors, and elevated serum levels of IgE. These transgenic mice demonstrate that TSLP can initiate a cascade of allergic inflammation in the skin and provide a valuable animal model for future study of this common disease.
doi:10.1084/jem.20041503
PMCID: PMC2212851  PMID: 16103410

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