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1.  Conditioning of naïve CD4+ T cells for enhanced peripheral Foxp3 induction by non-specific bystander inflammation 
Nature immunology  2016;17(3):297-303.
Summary
Inflammation induced during infection can both promote and suppress immunity. This contradiction suggests that inflammatory cytokines impact the immune system in a context-dependent manner. Here we show that non-specific bystander inflammation conditioned naïve CD4+ T cells for enhanced peripheral Foxp3 induction and reduced effector differentiation. This resulted in inhibition of immune responses in vivo via Foxp3-dependent effect on antigen-specific naïve CD4+ T cell precursors. Such conditioning may have evolved to allow immunity to infection while limiting subsequent autoimmunity caused by release of self-antigens in the wake of infection. Furthermore, this phenomenon suggests a mechanistic explanation for the concept that early tuning of the immune system by infection impacts the long-term quality of immune regulation.
doi:10.1038/ni.3329
PMCID: PMC4757503  PMID: 26752376
2.  Bronchoalveolar Lavage and Lung Tissue Digestion 
Bio-protocol  2013;3(16):e859.
Bronchoalveolar lavage (BAL) is a simple but valuable and typically performed technique commonly used for studying the pathogenesis of lung diseases such as asthma and COPD. Cell counts can be combined with new methods for examining inflammatory responses, such as ELISA, Flow cytometric analysis, immunohistochemistry, quantitative polymerase chain reaction, and HPLC to assess cellular expression for inflammatory cytokines and growth factor. Here we describe a basic procedure to collect BAL fluid and digest lung tissue for assessing a number of pulmonary components.
PMCID: PMC4933514  PMID: 27390755
3.  Acute blockade of IL-25 in a colitis associated colon cancer model leads to increased tumor burden 
Scientific Reports  2016;6:25643.
Chronic inflammation within the gastrointestinal tract results in an increased risk for developing colorectal cancer. Epithelial cytokines, including interleukin-25 (IL-25), are produced in the colon and are critical for protection from parasites, but can also be pathogenic in the context of inflammatory bowel diseases and allergy. Whether IL-25 is involved in the progression from inflammation to cancer is still largely unexplored. Using a well-established murine model for colitis-induced colon cancer; we aimed to determine the role of IL-25 in this process. We found that acute IL-25 blockade resulted in greater tumor burdens compared to isotype control treated mice. Histologically, α-IL-25 treated mice had increased colitis scores compared to mice receiving isotype control antibody, as well as decreased eosinophilia. This is the first study to explore the therapeutic potential of using an IL-25 blocking antibody during a chronic inflammatory setting. Taken together these data suggest that IL-25 plays an inhibitory role in the growth and development of colonic tumors.
doi:10.1038/srep25643
PMCID: PMC4863374  PMID: 27165713
4.  Thymic stromal lymphopoietin–mediated epicutaneous inflammation promotes acute diarrhea and anaphylaxis 
The Journal of Clinical Investigation  2014;124(12):5442-5452.
Atopic dermatitis (AD) and food allergy are closely linked; however, the mechanisms that guide the progression of AD to allergic inflammatory responses at other mucosal surfaces, including the gastrointestinal tract, are not well understood. Here, we determined that exposure of mice that have been epicutaneously sensitized with thymic stromal lymphopoietin (TSLP) and antigen to repeated oral doses of the same antigen induced acute diarrhea and anaphylaxis. In this model, loss of TSLP signaling specifically in DCs led to loss of induced allergic diarrhea through lack of sensitization. While TSLP responses were not required during oral allergen challenge, CD4+ T cells were required and transferred disease when introduced into naive hosts. In addition, oral exposure to the antigen prior to skin sensitization blocked development of allergic disease. Finally, mice lacking the receptor for IL-25 failed to develop acute diarrhea and anaphylaxis, highlighting a role for IL-25 in the initiation of type 2 immunity in the intestine. These results demonstrate a role for TSLP and IL-25 in the atopic march from skin sensitization to food allergic responses and provide a model system for the generation of potential therapeutic interventions.
doi:10.1172/JCI77798
PMCID: PMC4348967  PMID: 25365222
5.  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
6.  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
7.  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
8.  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
9.  Thymic Stromal Lymphopoietin (TSLP) and Cancer 
Originally shown to promote the growth and activation of B cells, thymic stromal lymphopoietin (TSLP) is now known to have wide-ranging effects on both hematopoietic and non-hematopoietic cell lineages. These include dendritic cells (DCs), basophils, 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. This review will highlight recent advances in the understanding of the surprising role of TSLP in the control of a variety of cancers, both solid tumors and leukemia, where the TSLP/TSLPR axis has been shown to be an important regulator.
doi:10.4049/jimmunol.1400864
PMCID: PMC4203400  PMID: 25326546
10.  Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling 
Background
The clarification of cutaneous dendritic cell subset and the role of thymic stromal lymphopoietin (TSLP) signaling in epicutaneous sensitization with protein antigens, as in the development of atopic dermatitis, is a crucial issue.
Objectives
Because TSLP is highly expressed in the vicinity of Langerhans cells (LCs), we sought to clarify our hypothesis that LCs play an essential role in epicutaneous sensitization with protein antigens through TSLP signaling.
Methods
By using Langerin-diphtheria toxin receptor knock-in mice and human Langerin-diphtheria toxin A transgenic mice, we prepared mice deficient in LCs. We also prepared mice deficient in TSLP receptors in LCs by using TSLP receptor–deficient mice with bone marrow chimeric technique. We applied these mice to an ovalbumin (OVA)-induced epicutaneous sensitization model.
Results
Upon the epicutaneous application of OVA, conditional LC depletion attenuated the development of clinical manifestations as well as serum OVA-specific IgE increase, OVA-specific T-cell proliferation, and IL-4 mRNA expression in the draining lymph nodes. Consistently, even in the steady state, permanent LC depletion resulted in decreased serum IgE levels, suggesting that LCs mediate the TH2 local environment. In addition, mice deficient in TSLP receptors on LCs abrogated the induction of OVA-specific IgE levels upon epicutaneous OVA sensitization.
Conclusion
LCs initiate epicutaneous sensitization with protein antigens and induce TH2-type immune responses via TSLP signaling.
doi:10.1016/j.jaci.2012.01.063
PMCID: PMC4600611  PMID: 22385635
Langerhans cell; TSLP; TSLP receptor; epicutaneous sensitization; protein antigen
11.  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
12.  Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components 
Background
Airway remodeling may explain lung function decline among asthmatic children. Extracellular matrix (ECM) deposition by human lung fibroblasts (HLFs) is implicated in airway remodeling. Airway epithelial cell (AEC) signaling may regulate HLF ECM expression.
Objectives
Determine whether AECs from asthmatic children differentially regulate HLF expression of ECM constituents.
Methods
Primary AECs were obtained from well-characterized atopic-asthmatic (N=10) and healthy children (N=10) intubated under anesthesia for an elective surgical procedure. AECs were differentiated at an air-liquid interface (ALI) for 3 weeks, then co-cultured with HLFs from a healthy child for 96 hours. Collagen I (COL1A1), collagen III (COL3A1), hyaluronan synthase 2 (HAS2), and fibronectin (FNDC) expression by HLFs and prostaglandin E2 synthase (PGE2S) expression by AECs was assessed by RT-PCR. TGFb1&2 concentrations in media were measured by ELISA.
Results
COL1A1 and COL3A1 expression by HLFs co-cultured with asthmatic AECs was greater than HLFs co-cultured with healthy AECs (2.2 fold, p<0.02; 10.8 fold, p<0.02). HAS2 expression by HLFs co-cultured with asthmatic AECs was 2.5-fold higher than by HLFs co-cultured with healthy AECs (p<0.002). FNDC expression by HLFs co-cultured with asthmatic AECs was significantly greater than by HLFs alone. TGFb2 activity was elevated in asthmatic AEC-HLF co-cultures (p<0.05) while PGES2 was down regulated in AEC-HLF co-cultures (2.2 fold, p<0.006).
Conclusions
HLFs co-cultured with asthmatic AECs showed differential expression of ECM constituents COL1A1 & COL3A1, and HAS2 compared to HLFs co-cultured with healthy AECs. These findings support a role for altered ECM production in asthmatic airway remodeling, possibly regulated by unbalanced AEC signaling.
doi:10.1016/j.jaci.2014.04.007
PMCID: PMC4149938  PMID: 24875618
asthma; children; airway remodeling; epithelial cells; human lung fibroblasts; extracellular matrix; collagen I; collagen III; hyaluronic acid; fibronectin; TGFb2
13.  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
14.  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
15.  Increased density of intraepithelial mast cells in exercise-induced bronchoconstriction regulated via epithelial-derived TSLP and IL-33 
Background
Exercise-induced bronchoconstriction (EIB) is a prototypical feature of indirect airway hyperresponsiveness (AHR). Mast cells are implicated in EIB, but the characteristics, regulation, and function of mast cells in EIB are poorly understood.
Objectives
To examine mast cell infiltration of the airway epithelium in EIB, and the regulation of mast cell phenotype and function by epithelial-derived cytokines.
Methods
Endobronchial biopsies, epithelial brushings, and induced sputum were obtained from asthmatics with and without EIB, and normal controls. Mast cell proteases were quantified by qPCR, and mast cell density by design-based stereology. Airway epithelial responses to wounding and osmotic stress were assessed in primary airway epithelial cells and ex vivo murine lung tissue. Mast cell granule development and function were examined in cord blood-derived mast cells.
Results
Tryptase and carboxypeptidase A3 (CPA3) expression in epithelial brushings and epithelial mast cell density were selectively elevated in the asthma group with EIB. A in vitro scratch wound initiated the release of TSLP that was greater in epithelial cells derived from asthmatics. Osmotic stress induced the release of IL-from explanted murine lung that was increased in allergen-treated mice. TSLP combined with IL-33 increased tryptase and CPA3 immunostaining in mast cell precursors, and selectively increased cysteinyl leukotriene formation by mast cells in a manner that was independent of in vitro sensitization.
Conclusions
Mast cell infiltration of the epithelium is a critical determinant of indirect AHR, and the airway epithelium may serve as an important regulator of the development and function of this mast cell population.
doi:10.1016/j.jaci.2013.08.052
PMCID: PMC4004718  PMID: 24220317
Asthma; Airway Hyperresponsiveness, Eicosanoid; Epithelial Cell; Leukotriene
16.  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
17.  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
18.  Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 (ILC2) and γδ T cells 
Immunity  2014;40(3):414-424.
SUMMARY
Chitin, a polysaccharide constituent of many allergens and parasites, initiates innate type 2 lung inflammation through incompletely defined pathways. We show that inhaled chitin induced expression of three epithelial cytokines, interleukin-25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP), which non-redundantly activated resident innate lymphoid type 2 cells (ILC2) to express IL-5 and IL-13 necessary for accumulation of eosinophils and alternatively activated macrophages (AAMs). In the absence of all three epithelial cytokines, ILC2 normally populated the lung but failed to increase IL-5 and IL-13. Although eosinophils and AAMs were attenuated, neutrophil influx remained normal without these epithelial cytokines. Genetic ablation of ILC2, however, enhanced IL-1β, TNFα and IL-23 expression, increased activation of IL-17A-producing γδ T cells, and prolonged neutrophil influx. Thus, chitin elicited patterns of innate cytokines that targeted distinct populations of resident lymphoid cells, revealing divergent but interacting pathways underlying the tissue accumulation of specific types of inflammatory myeloid cells.
doi:10.1016/j.immuni.2014.02.003
PMCID: PMC4019510  PMID: 24631157
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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