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.
TSLP; asthma; allergy; atopic dermatitis; inflammation
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.
TSLP; TSLPR; RSV; asthma; epithelium
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.
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.
TSLPR; TSLP; Th2 cell; IL-4
Regulatory T (Treg) cells, driven by the Foxp3 transcription factor, are responsible for limiting autoimmunity and chronic inflammation. We showed that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg cell development and in vitro function are not markedly altered in Foxp3gfp NOD and C57BL/6 mice, Treg cell function in inflammatory environments was perturbed and TGFβ-induced Treg cell development was reduced. Foxp3gfp was unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which led to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this results in an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg cell insufficiency that enables autoimmunity in susceptible environments.
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.
Cytokines; Allergy; Inflammation; Lung
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.
Psoriasis is an immune-mediated chronic inflammatory skin disease, characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. IL-23 is expressed in psoriatic skin, and IL-23 injected into the skin of mice produces IL-22-dependent dermal inflammation and acanthosis. The chemokine receptor CCR2 has been implicated in the pathogenesis of several inflammatory diseases, including psoriasis. CCR2-positive cells and the CCR2 ligand, CCL2 are abundant in psoriatic lesions. To examine the requirement of CCR2 in the development of IL-23-induced cutaneous inflammation, we injected the ears of wild-type (WT) and CCR2-deficient (CCR2−/−) mice with IL-23. CCR2−/− mice had increased ear swelling and epidermal thickening, which was correlated with increased cutaneous IL-4 levels and increased numbers of eosinophils within the skin. In addition, TSLP, a cytokine known to promote and amplify T helper cell type 2 (Th2) immune responses, was also increased within the inflamed skin of CCR2−/− mice. Our data suggest that increased levels of TSLP in CCR2−/− mice may contribute to the propensity of these mice to develop increased Th2-type immune responses.
The cytokine thymic stromal lymphopoietin (TSLP) functions as a regulator of bone marrow B-cell development and a key initiator of allergic inflammation. In the current study, we show that mature B cells, derived from transgenic mice with systemically elevated levels of TSLP (K5-TSLP mice), exhibit markedly enhanced mitogenic responses in vitro and that this enhanced responsiveness leads to polyclonal B-cell activation and development of autoimmune hemolytic anemia in vivo. In contrast, B cells derived from K5-TSLP mice lacking CD4+ T cells failed to show polyclonal activation. Furthermore, neither mature B-cell activation nor hemolytic anemia occurred in IL-4-deficient K5-TSLP mice. Consistent with these findings, activation of mature B cells occurred independently of B-cell intrinsic TSLP signals. Taken together, our results demonstrate that systemic alterations in TSLP, through induction of IL-4 from CD4+ T cells and other cell types, functions as an important factor in peripheral B-cell homeostasis and promotion of humoral autoimmunity.
autoantibody; cytokine; hemolytic anemia; Th2
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.
Th1/Th2 Cells; Inflammation; Allergy; Dendritic Cells; Rodent
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.
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.
FOXP3; Regulatory T Cell; Th17
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.
TSLP; atopic dermatitis; atopic march; mouse model
Thymic stromal lymphopoetin (TSLP) influences numerous immune functions, including those in the colonic mucosa. Here we report that TSLP-deficient (Tslp-/-) mice, did not exhibit increased inflammation during dextran sodium sulfate (DSS)-induced colitis, but failed to recover from disease, resulting in death. Increased localized neutrophil elastase (NE) activity during overt inflammation was observed in Tslp-/- mice, and was paralleled by reduced expression of an endogenous inhibitor, secretory leukocyte peptidase inhibitor (SLPI). Pharmacological inhibition of NE, or treatment with rSLPI reduced DSS-induced mortality in Tslp-/- mice. Signaling through TSLPR on non-hematopoietic cells was sufficient for recovery from DSS-induced colitis. Expression of the receptor occurred on intestinal epithelial cells (IEC), with stimulation inducing SLPI expression. Therefore, TSLP is critical in mediating mucosal healing following insult, and functions in a non-redundant capacity that is independent of restraining T helper 1 (Th1) and Th17 cell cytokine production.
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.
CD4+CD25+ regulatory T (TR) cells have been described in both humans and mice. In mice, TR are thymically derived, and lack of TR leads to organ-specific autoimmunity. Recently, the forkhead/winged helix transcription factor, FoxP3, has been shown to be important for the function of TR cells in mice. In this study, human TR cells were examined and, in results similar to those of studies done in mice, expression of FoxP3 was found exclusively in CD4+CD25+ T cells and correlated with the suppressive activity of these cells. In contrast to the mouse studies, activation of human CD4+CD25– T cells led to expression of FoxP3. Expression of FoxP3 in activated human CD4+CD25+ cells also correlated with suppression of proliferation by these cells in freshly isolated CD4+CD25– T cells from the same donor. This suppression was cell-contact dependent and cytokine independent. Thus, in humans, during activation of CD4+CD25– T cells in an immune response, two populations of cells may arise, effector CD4+CD25+ and regulatory CD4+CD25+ T cells, with expression of FoxP3 correlated with regulatory activity. These data also raise the possibility that a failure to generate peripheral TR cells properly may contribute to autoimmune disease and suggest a possible therapeutic role for FoxP3 in the treatment of such diseases.
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.
TSLP; Th2 cytokine responses; innate immunity; basophils; hematopoiesis
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 atopy and atopic diseases. This review will discuss this work and place TSLP in the inflammatory cascade that leads to allergic disease.
Airway tolerance is critical for protecting the lung from inflammatory disease driven by allergens. However, factors that disrupt tolerance processes and then lead to susceptibility to developing allergic asthma remain elusive.
To investigate whether recognition of bacterial microbial-associated molecular patterns in the lung may result in susceptibility to developing allergic reactions, and to understand the molecular mechanisms by which such triggers block natural tolerance.
Ligands of intracellular microbial-associated molecular pattern recognition receptors – the Nod-like receptors (NLRs), Nod1 and Nod2 - were given intranasally with antigen and their ability to modulate airway tolerance was analyzed.
Intranasal Nod2 ligand rapidly induced lung expression of the innate cytokines TSLP and IL-25, and TSLP promoted expression of OX40L, a T cell costimulatory ligand, on lung CD11c+CD11b+ cells and B220+ cells. Together these three molecules blocked the generation of antigen-specific CD4+Foxp3+ adaptive Treg, and concomitantly drove IL-4-producing CD4 T cells. By altering the Treg/Th2 balance, tolerance was blocked and sensing of Nod2 ligand then resulted in subsequent susceptibility to developing eosinophil-dominated airway inflammation.
We show that a Nod-like receptor is a novel, previously unrecognized, pathway that adversely links innate and adaptive immunity and leads to allergic disease and asthmatic lung inflammation.
Mouse; Nod2; asthma; TSLP; OX40L; IL-25; regulatory T cell
Atopic dermatitis (AD) is characterized by intense scratching and a Th2 dominated systemic and local immune response to cutaneously introduced antigens. Because scratching inflicts mechanical injury to the skin, we examined the effect of mechanical injury inflicted by tape stripping on the capacity of skin dendritic cells (DCs) to polarize T cells towards a Th2 phenotype. DCs isolated from skin 6 hrs after tape stripping elicited significantly higher production of IL-4 and IL-13, and significantly lower production of interferon-γ (IFN-γ) by OVA stimulated CD4+ DO.11.10 cells, than DCs isolated from unmanipulated skin, and expressed significantly more mRNA for the Th2 skewing molecules IL-10 and the Notch ligands Jagged1 and Jagged2, but significantly less mRNA for the Th1 skewing cytokine IL-12. CD11c+FITC+ cells isolated from draining lymph nodes (DLN) of shaved and tape stripped mouse skin 24 hrs after painting with FITC polarized T cells towards Th2 significantly more than CD11c+FITC+ cells isolated from DLN of shaved non tape stripped skin, and expressed significantly more IL-10, Jagged1 and Jagged2 mRNA, but significantly less IL-12 mRNA. Tape stripping significantly increased TSLP levels in the skin. Studies in TSLPR−/− mice demonstrated that TSLP played an essential role in the Th2 polarization effect of tape stripping on skin DCs. These results suggest that mechanical injury inflicted by scratching in patients with AD polarizes skin DCs to elicit a Th2 response by upregulating local expression of TSLP.
The molecule H22-Fel d 1, which targets cat allergen to FcγRI on dendritic cells, has the potential to treat cat allergy owing to its T-cell modulatory properties.
To investigate whether the T-cell response induced by H22-Fel d 1 is altered in the presence of the Th2-promoting cytokine, TSLP.
Studies were performed in cat-allergic subjects with and without atopic dermatitis. Monocyte-derived dendritic cells were primed with H22-Fel d 1 in the presence or absence of TSLP and the resulting T-cell cytokine repertoire was analyzed by flow cytometry. The capacity for H22-Fel d 1 to modulate TSLP receptor expression on dendritic cells was examined by flow cytometry in the presence or absence of inhibitors of Fc receptor signaling molecules.
Surprisingly, TSLP alone was a weak inducer of Th2 responses irrespective of atopic status; however, dendritic cells co-primed with TSLP and H22-Fel d 1 selectively and synergistically amplified Th2 responses in highly atopic subjects. This effect was OX40 ligand-independent pointing to an unconventional TSLP-mediated pathway. Expression of TSLP receptor was upregulated on atopic dendritic cells primed with H22-Fel d 1 through a pathway regulated by FcγRI-associated signaling components, including src related tyrosine kinases and Syk, as well as the downstream molecule, PI3-kinase. Inhibition of TSLP receptor upregulation triggered by H22-Fel d 1 blocked TSLP-mediated Th2 responses.
Discovery of a novel Th2 regulatory pathway linking FcγRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines.
This study establishes a pivotal role for Fc receptor ligation in promoting TSLP-mediated Th2 responses associated with allergic disease.
Atopic dendritic cells are equipped to efficiently upregulate TSLP receptor upon Fc receptor ligation by allergen. These findings suggest that dendritic cell-based vaccines that target Fc receptors could amplify Th2-driven inflammatory responses by potentiating the effects of TSLP.
H22-Fel d 1; TSLP; TSLP receptor; atopic dermatitis; blood dendritic cells; monocyte-derived dendritic cells; Th2 cells; FcγRI
Atopic dermatitis (AD) is characterized by scratching and by Th2-dominated immune response to cutaneously introduced antigens. Antigen application to skin mechanically injured by tape stripping results in Th2-dominated skin inflammation.
To examine the effect of tape stripping on the capacity of skin dendritic cells (DCs) to polarize T cells towards a Th2 phenotype.
CD11c+ DCs were isolated from skin of BALB/c or C57BL/6 mice. FITC+ and FITC− DCs were isolated from draining lymph nodes (DLN) 24 hrs after painting the skin with FITC. DCs were assessed for their ability to induce cytokine secretion by OVA stimulated naïve CD4+ T cells from TCR-OVA transgenic DO11.10 mice. Cytokine mRNA levels were examined by quantitative PCR.
DCs isolated from the skin of wild-type (WT), but not TSLPR−/− or IL-10−/−, mice 6 hrs after tape stripping elicited significantly more IL-4 and IL-13, and significantly less interferon-γ production by CD4+ cells, than DCs isolated from unmanipulated skin, and expressed significantly more mRNA for the Th2 skewing molecules IL-10, Jagged1, and Jagged2, but significantly less mRNA for the Th1 skewing cytokine IL-12. CD11c+FITC+ cells isolated from DLN of shaved and tape stripped skin of WT, but not TSLPR−/− or IL-10−/−, mice polarized T cells significantly more towards Th2 and expressed significantly more IL-10, Jagged1 and Jagged2 mRNA than CD11c+FITC+ cells isolated from DLN of shaved skin. Tape stripping significantly increased TSLP levels in the skin, and TSLP was shown to play an essential role in the Th2 polarization of skin DCs by tape stripping.
Tape stripping upregulates TSLP levels in the skin, which polarizes skin DCs to elicit a Th2 response via the induction of IL-10.
Mechanical injury inflicted by scratching in patients with AD may cause skin DCs to polarize T cells to secrete Th2 cytokines.
Mechanical injury to the skin, such as that caused by scratching in AD, may cause skin DCs to polarize T cells to secrete more allergy-mediating Th2 cytokines.
Atopic dermatitis; scratching; mechanical injury; thymic stromal lymphopoietin; IL-10; Th2 cytokines
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.
Lung-specific TSLP expression is sufficient for the development of an asthma-like chronic airway inflammatory disease. However, the nature of the downstream pathways that regulate disease development are not known. In this study, we used IL-4- and Stat6-deficient mice to establish the role of Th2-type responses downstream of TSLP. IL-4 deficiency greatly reduced, but did not eliminate, TSLP induced airway hyperresponsiveness (AHR), airway inflammation, eosinophilia and goblet cell metaplasia, while Stat6 deficiency eliminated these asthma-like symptoms. We further demonstrate, using the chronic model of TSLP-mediated airway inflammation, that blockade of both IL-4 and IL-13 responses, through administration of an anti-IL-4Rα monoclonal antibody, reversed asthma-like symptoms, when given to mice with established disease. Collectively these data provide insight into the pathways engaged in TSLP driven airway inflammation and demonstrate that simultaneous blockade of IL-4 and IL-13 can reverse established airway disease, suggesting that this may be an effective approach for the therapy of Th2-mediated inflammatory respiratory disease.
Th1/Th2 cells; cytokines; lung; inflammation
Thymic stromal lymphopoietin was recently identified as a master switch for the development of allergen-driven Th2 responses. However, the role of thymic stromal lymphopoietin (TSLP) in the development of helminth-induced Th2 responses is unclear. Here, using TSLPR−/− mice, we show that while TSLPR signaling participates in the development of Schistosoma mansoni egg-induced CD4+ Th2 responses, it plays only a transient role in the development of Th2-dependent pathology in the lung, liver, and intestine. Studies conducted in a pulmonary granuloma model showed that while a reduction in IL-4/IL-13-dependent granulomatous inflammation and tissue eosinophilia was observed in TSLPR−/− mice undergoing a primary response, lesion formation was not affected during a secondary granulomatous response, even though IL-5 and IL-13 were modestly reduced in the knockout mice. To evaluate the importance of TSLPR signaling in the development of a chronic Th2-dependent response, TSLPR−/− mice were also infected with S. mansoni cercariae. Here, the only significant difference noted in TSLPR−/− mice was a modest decrease in liver fibrosis in acutely infected animals. The transient decrease in fibrosis was associated with increased production of the antifibrotic cytokine IFN-γ and decreased production of the profibrotic cytokine IL-13. Although the altered cytokine response persisted in chronically infected TSLPR−/− mice, it failed to reduce granuloma formation or fibrosis, confirming that TSLPR signaling plays a limited role in the development of chronic Th2-dependent pathology. Collectively, these findings suggest that while TSLPR signaling serves a key role in allergen-driven Th2 responses, it exerts minor regulatory activity during this chronic helminth infection.