Suppression Of Allergic Airway Inflammation Research Articles

Immunomodulatory Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Allergic Airway Disease.

Mesenchymal stem cells (MSCs) have been reported as promising candidates for the treatment of various diseases, especially allergic diseases, as they have the capacity to differentiate into various cells. However, MSCs itself have several limitations such as creating a risk of aneuploidy, difficulty in handling them, immune rejection, and tumorigenicity, so interest in the extracellular vesicles (EVs) released from MSCs are increasing, and many studies have been reported. Previous studies have shown that extracellular vesicles (EVs) produced by MSCs are as effective as the MSCs themselves in suppression of allergic airway inflammation through the suppression of Th2 cytokine production and the induction of regulatory T cells (Treg) expansion. EVs are one of the substances secreted by paracrine induction from MSCs, and because it exerts its effect by delivering contents such as mRNA, microRNA, and proteins to the receptor cell, it can reduce the problems or risks related to stem cell therapy. This article reviews the immunomodulatory properties of MSCs-derived EVs and their therapeutic implications for allergic airway disease.

Intranasal delivery of allergen in a nanoemulsion adjuvant inhibits allergen-specific reactions in mouse models of allergic airway disease.

Atopic diseases are an increasing problem that involve both immediate hypersensitivity reactions mediated by IgE and unique cellular inflammation. Many forms of specific immunotherapy involve the administration of allergen to suppress allergic immune responses but are focused on IgE-mediated reactions. In contrast, the effect of allergen-specific immunotherapy on allergic inflammation is complex, not entirely consistent and not well understood. We have previously demonstrated the ability of allergen administered in a nanoemulsion (NE) mucosal adjuvant to suppress IgE-mediated allergic responses and protect from allergen challenge in murine food allergy models. This activity was associated with decreases in allergen-specific IL-10 and reductions in allergic cytokines and increases in regulatory T cells. Here, we extend these studies to using 2 distinct models, the ovalbumin (OVA) and cockroach (CRA) models of allergic airway disease, which are based predominantly on allergic inflammation. Acute or chronic allergic airway disease was induced in mice using ovalbumin and cockroach allergen models. Mice received three therapeutic immunizations with allergen in NE, and reactivity to airway challenge was determined. Therapeutic immunization with cockroach or OVA allergen in NE markedly reduced pathology after airway challenge. The 2 models demonstrated protection from allergen challenge-induced pathology that was associated with suppression of Th2-polarized immune responses in the lung. In addition, the reduction in ILC2 numbers in the lungs of allergic mice along with reduction in epithelial cell alarmins, IL-25 and IL-33, suggests an overall change in the lung immune environment induced by the NE immunization protocol. These results demonstrate that suppression of allergic airway inflammation and bronchial hyper-reactivity can be achieved using allergen-specific immunotherapy without significant reductions in allergen-specific IgE and suggest that ILC2 cells may be critical targets for this activity.

Screening and Functional Pathway Analysis of Pulmonary Genes Associated with Suppression of Allergic Airway Inflammation by Adipose Stem Cell-Derived Extracellular Vesicles.

Background Although mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) are as effective as MSCs in the suppression of allergic airway inflammation, few studies have explored the molecular mechanisms of MSC-derived EVs in allergic airway diseases. The objective of this study was to evaluate differentially expressed genes (DEGs) in the lung associated with the suppression of allergic airway inflammation using adipose stem cell- (ASC-) derived EVs. Methods C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. To evaluate the effect of ASC-derived EVs on allergic airway inflammation, 10 μg/50 μL of EVs were administered intranasally prior to OVA challenge. Lung tissues were removed and DEGs were compared pairwise among the three groups. DEG profiles and hierarchical clustering of the identified genes were analyzed to evaluate changes in gene expression. Real-time PCR was performed to determine the expression levels of genes upregulated after treatment with ASC-derived EVs. Enrichment analysis based on the Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also performed to further identify the function of DEGs. Results Expression of paraoxonase 1 (PON1), brain-expressed X-linked 2 (Bex2), insulin-like growth factor binding protein 6 (Igfbp6), formyl peptide receptor 1 (Fpr1), and secretoglobin family 1C member 1 (Scgb1c1) was significantly increased in asthmatic mice following treatment with ASC-derived EVs. GO enrichment and KEGG pathway analysis showed that these genes were strongly associated with immune system processes and their regulation, cellular processes, single-organism processes, and biological regulation. Conclusion These results suggest that the DEGs identified in this study (PON1, Bex2, Igfbp6, Fpr1, and Scgb1c1) may be involved in the amelioration of allergic airway inflammation by ASC-derived EVs.

Application of Stem Cell-Derived Extracellular Vesicles in Allergic Airway Diseases

Mesenchymal stem cells (MSCs) have been reported to be promising candidates for the treatment of allergic airway diseases. However, MSCs themselves have several problems including immune rejection, risk of aneuploidy, difficulty of handling, and tumorigenicity. An increasing number of studies demonstrated that administration of conditioned media or extracellular vesicles (EVs) released by MSCs is as effective as the MSCs themselves in suppression of allergic airway inflammation. EVs can exert their effects by delivering their contents such as proteins, mRNAs, and microRNAs to recipient cells. Furthermore, the administration of MSCs-derived EVs may reduce potential safety risks associated with stem cell therapy, suggesting that MSCs-derived EVs may be a promising alternative to cell therapy for allergic airway diseases. This review examines the current understanding of the immunomodulatory properties of MSCs-derived EVs and its therapeutic implication for allergic airway diseases.

Inhibition of phosphodiesterase suppresses allergic lung inflammation by regulating MCP-1 in an OVA-induced asthma murine model with co-exposure to lipopolysaccharide.

ObjectiveAsthma is a chronic inflammatory disease that can lead to severe problems with the respiratory system. This study aimed to evaluate the suppression of allergic airway inflammation of an asthma murine model by 3-isobutyl-1-methylxanthine (IBMX), which is a non-specific cyclic nucleotide phosphodiesterase (PDE) inhibitor.MethodsAllergic lung inflammation was evoked by ovalbumin (OVA) alone or co-exposure with lipopolysaccharide (LPS) in a murine asthma model.ResultsCompared with the OVA alone-treated control, co-exposure with LPS significantly enhanced allergic inflammatory responses in airway hyperresponsiveness and pathologic changes of the asthmatic mouse lung. Specifically, LPS enhanced allergic asthma through the increase of monocyte chemoattractant protein (MCP)-1 release. However, IBMX significantly suppressed specific airway resistance and tidal volume, the infiltration of eosinophils and mast cells into the lung, the levels of serum immunoglobulin (Ig)E and IgG1, and the release of Th2 cytokines (interleukin (IL)-4, IL-13, and MCP-1). IBMX attenuated the aggravation of inflammation by inhibiting MCP-1, and inhibited the infiltration of eosinophils and the production of Th2 cell-associated inflammatory mediators.ConclusionThese results demonstrate the therapeutic potential of targeting the regulation of PDE activity in an aggravated chronic allergic asthmatic response after bacterial infection.

Suppression of allergic airway inflammation by MCPIP1 through suppression of IL-5-producing Th2 cells

Abstract Allergic inflammation is mediated mainly through production of Th2 cytokines (IL-4, IL-5 and IL-13). Though we have learned much about how Th2 cells are differentiated, our understanding of the Th2 checkpoint mechanisms remains elusive. We recently found that a new RNA-binding protein, monocyte chemotactic protein induced protein-1 (MCPIP1, also named Regnase-1, encoded by Zc3h12a), suppresses Th2 differentiation and Th2 inflammation. Zc3h12a−/− mice spontaneously develop severe airway inflammation similar to asthma patients, with an increase mainly in IL-5- and IL-13-producing Th2 cells in the airway. Zc3h12a−/−CD4 T cells are mostly effector T cells and produce significant amounts of IL-5 and IL-13 but not IL-4. We further found that the differentiation of IL-5/IL-13-producing CD4 T cells is independent of IL-4 in Zc3h12a−/−naïve CD4 T cells. IL-5 expression correlates with the levels of GATA3 in Zc3h12a−/− CD4 T cells. Overexpression of MCPIP1 inhibits GATA3 and IL-5 expression through promoting GATA3 mRNA decay via RNase and CCCH domains. Furthermore, deletion of MCPIP1 in mice results in a significant increase in OVA-specific Th2 cells and severe Th2 inflammation in the airway of receipt mice after T cell transfer. Our study reveals that MCPIP1 is a potent regulator for Th2 development and function, especially the IL-5/IL-13-producing Th2 cells. MCPIP1 is a potentially new target for treatment of asthma and other Th2-mediated allergic diseases.

Bacillus subtilis-mediated suppression of house dust mite allergic airway inflammation

Abstract The incidence of allergic diseases is increasing, with house dust mite allergy, afflicting up to 20% of the population in developed countries. House dust mites (HDM) are a common allergen that can be difficult to avoid and can trigger allergic reactions, including wheezing and shortness of breath. We recently showed that two pretreatments with Bacillus subtilis, a gram-positive bacterium, can prevent murine HDM-induced allergic lung inflammation. We assessed infiltration of eosinophils in bronchial alveolar lavage fluid and found significantly reduced eosinophils following B. subtilis treatment. Our current work addresses the capacity of B. subtilis to provide long-term protection from HDM challenge. Following pretreatment with B. subtilis, we found protection from HDM challenge, determined by quantifying infiltrating eosinophils for two weeks, but lost protection after three weeks. These data suggest a transient protection elicited by B. subtilis and support the need for frequent dosing to maintain suppression of allergic airway inflammation.

Use of Polymeric Nanoparticle Platform Targeting the Liver To Induce Treg-Mediated Antigen-Specific Immune Tolerance in a Pulmonary Allergen Sensitization Model.

Nanoparticles (NPs) can be used to accomplish antigen-specific immune tolerance in allergic and autoimmune disease. The available options for custom-designing tolerogenic NPs include the use of nanocarriers that introduce antigens into natural tolerogenic environments, such as the liver, where antigen presentation promotes tolerance to self- or foreign antigens. Here, we demonstrate the engineering of a biodegradable polymeric poly(lactic- co-glycolic acid) (PLGA) nanocarrier for the selective delivery of the murine allergen, ovalbumin (OVA), to the liver. This was accomplished by developing a series of NPs in the 200-300 nm size range as well as decorating particle surfaces with ligands that target scavenger and mannose receptors on liver sinusoidal endothelial cells (LSECs). LSECs represent a major antigen-presenting cell type in the liver capable of generating regulatory T-cells (Tregs). In vitro exposure of LSECs to NPOVA induced abundant TGF-β, IL-4, and IL-10 production, which was further increased by surface ligands. Animal experiments showed that, in the chosen size range, NPOVA was almost exclusively delivered to the liver, where the colocalization of fluorescent-labeled particles with LSECs could be seen to increase by surface ligand decoration. Moreover, prophylactic treatment with NPOVA in OVA-sensitized and challenged animals (aerosolized inhalation) could be seen to significantly suppress anti-OVA IgE responses, airway eosinophilia, and TH2 cytokine production in the bronchoalveolar lavage fluid. The suppression of allergic airway inflammation was further enhanced by attachment of surface ligands, particularly for particles decorated with the ApoB peptide, which induced high levels of TGF-β production in the lung along with the appearance of Foxp3+ Tregs. The ApoB-peptide-coated NPs could also interfere in allergic airway inflammation when delivered postsensitization. The significance of these findings is that liver and LSEC targeting PLGA NPs could be used for therapy of allergic airway disease, in addition to the potential ofusing their tolerogenic effects for other disease applications.

Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83

Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83

Indoleamine 2,3-Dioxygenase Is Not a Pivotal Regulator Responsible for Suppressing Allergic Airway Inflammation through Adipose-Derived Stem Cells.

BackgroundAlthough indoleamine 2,3-dioxygenase (IDO)-mediated immune suppression of mesenchymal stem cells (MSCs) has been revealed in septic and tumor microenvironments, the role of IDO in suppressing allergic airway inflammation by MSCs is not well documented. We evaluated the effects of adipose-derived stem cells (ASCs) on allergic inflammation in IDO-knockout (KO) asthmatic mice or asthmatic mice treated with ASCs derived from IDO-KO mice.Methods and FindingsASCs were injected intravenously in wild-type (WT) and IDO-KO asthmatic mice. Furthermore, asthmatic mice were injected with ASCs derived from IDO-KO mice. We investigated the immunomodulatory effects of ASCs between WT and IDO-KO mice or IDO-KO ASCs in asthmatic mice. In asthmatic mice, ASCs significantly reduced airway hyperresponsiveness, the number of total inflammatory cells and eosinophils in bronchoalveolar lavage fluid (BALF), eosinophilic inflammation, goblet hyperplasia, and serum concentrations of total and allergen-specific IgE and IgG1. ASCs significantly inhibited Th2 cytokines, such as interleukin (IL)-4, IL-5, and IL-13, and enhanced Th1 cytokine (interferon-γ) and regulatory cytokines (IL-10, TGF-β) in BALF and lung draining lymph nodes (LLNs). ASCs led to significant increases in regulatory T-cells (Tregs) and IL-10+ T cell populations in LLNs. However, the immunosuppressive effects of ASCs did not significantly differ between WT and IDO-KO mice. Moreover, ASCs derived from IDO-KO mice showed immunosuppressive effects in allergic airway inflammation.ConclusionsIDO did not play a pivotal role in the suppression of allergic airway inflammation through ASCs, suggesting that it is not the major regulator responsible for suppressing allergic airway inflammation.

Prostaglandin E2 and Transforming Growth Factor-β Play a Critical Role in Suppression of Allergic Airway Inflammation by Adipose-Derived Stem Cells.

BackgroundThe role of soluble factors in the suppression of allergic airway inflammation by adipose-derived stem cells (ASCs) remains to be elucidated. Moreover, the major soluble factors responsible for the immunomodulatory effects of ASCs in allergic airway diseases have not been well documented. We evaluated the effects of ASCs on allergic inflammation in asthmatic mice treated with a prostaglandin E2 (PGE2) inhibitor or transforming growth factor-β (TGF-β) neutralizing antibodies.Methods and FindingsAsthmatic mice were injected intraperitoneally with a PGE2 inhibitor or TGF-β neutralizing antibodies at approximately the same time as ASCs injection and were compared with non-treated controls. In asthmatic mice, ASCs significantly reduced airway hyperresponsiveness, the number of total inflammatory cells and eosinophils in the bronchoalveolar lavage fluid (BALF), eosinophilic inflammation, goblet cell hyperplasia, and serum total and allergen-specific IgE and IgG1. ASCs significantly inhibited Th2 cytokines, such as interleukin (IL)-4, IL-5, and IL-13, and enhanced the Th1 cytokine (Interferon-γ) and regulatory cytokines (IL-10 and TGF-β) in the BALF and lung draining lymph nodes (LLNs). ASCs engraftment caused significant increases in the regulatory T cell (Treg) and IL-10+ T cell populations in LLNs. However, blocking PGE2 or TGF-β eliminated the immunosuppressive effect of ASCs in allergic airway inflammation.ConclusionsASCs are capable of secreting PGE2 and TGF-β, which may play a role in inducing Treg expansion. Furthermore, treatment with a PGE2 inhibitor or TGF-β neutralizing antibodies eliminated the beneficial effect of ASCs treatment in asthmatic mice, suggesting that PGE2 and TGF-β are the major soluble factors responsible for suppressing allergic airway inflammation.

A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice

BackgroundCpG-containing oligodeoxynucleotides (CpG-ODNs) are potent inhibitors of T helper 2 mediated allergic airway disease in sensitised mice challenged with allergen. A single treatment has transient effects but a limited series...

Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells

The continual rise of asthma in industrialised countries stands in strong contrast to the situation in developing lands. According to the modified Hygiene Hypothesis, helminths play a major role in suppressing bystander immune responses to allergens, and both epidemiological and experimental studies suggest that the tropical parasitic trematode Schistosoma mansoni elicits such effects. The focus of this study was to investigate which developmental stages of schistosome infection confer suppression of allergic airway inflammation (AAI) using ovalbumin (OVA) as a model allergen. Moreover, we assessed the functional role and localization of infection-induced CD4+Foxp3+ regulatory T cells (Treg) in mediating such suppressive effects. Therefore, AAI was elicited using OVA/adjuvant sensitizations with subsequent OVA aerosolic challenge and was induced during various stages of infection, as well as after successful anti-helminthic treatment with praziquantel. The role of Treg was determined by specifically depleting Treg in a genetically modified mouse model (DEREG) during schistosome infection. Alterations in AAI were determined by cell infiltration levels into the bronchial system, OVA-specific IgE and Th2 type responses, airway hyper-sensitivity and lung pathology. Our results demonstrate that schistosome infection leads to a suppression of OVA-induced AAI when mice are challenged during the patent phase of infection: production of eggs by fecund female worms. Moreover, this ameliorating effect does not persist after anti-helminthic treatment, and depletion of Treg reverts suppression, resulting in aggravated AAI responses. This is most likely due to a delayed reconstitution of Treg in infected-depleted animals which have strong ongoing immune responses. In summary, we conclude that schistosome-mediated suppression of AAI requires the presence of viable eggs and infection-driven Treg cells. These data provide evidence that helminth derived products could be incorporated into treatment strategies that specifically target suppression of immune responses in AAI by inducing Treg cells.

Allergen-Specific CTL Require Perforin Expression To Suppress Allergic Airway Inflammation

Allergen-specific CTL have a protective effect on allergic airway inflammation, a function thought to be mediated by cytokines, especially IFN-γ. However, the contribution of cytotoxic function to this protective effect has not been investigated. We examined the contribution of cytotoxic function to the therapeutic effect of allergen-specific CTL in allergic airway inflammation. We used a murine model of allergic airway inflammation in which mice were sensitized to OVA and then challenged with the same Ag via the intranasal route. CTL were elicited in these mice by immunization with dendritic cells (DC) or by adoptive transfer of in vitro-activated CD8(+) T cells. Hallmark features of allergic asthma, such as infiltration of eosinophils in the bronchoalveolar lavage fluid and mucus production, were assessed. Suppression of allergic airway inflammation by allergen-specific CTL was critically dependent on the expression of perforin, a key component of the cytotoxic machinery. Both perforin-sufficient and perforin-deficient allergen-specific CTL were recovered from the lungs of allergen-sensitized mice and upregulated CD69 expression and secreted the cytokines IFN-γ and TNF-α upon intranasal allergen challenge. However, only perforin-sufficient CTL inhibited eosinophil infiltration in the airway, mucus production, and cytokine accumulation in the bronchoalveolar lavage fluid. Treatment with allergen-specific CTL, but not their perforin-deficient counterparts, was also associated with a decrease in the number of DC in the mediastinal lymph node. Our data suggest that the cytotoxic function of allergen-specific CD8(+) T cells is critical to their ability to moderate allergic airway inflammation.

Suppression of Allergic Airway Inflammation by Low Dose, Intranasally Administered Der p 1 Derived Peptides, in a Murine Model of House Dust Mite Allergy

Recently, we demonstrated the induction of immune tolerance in a murine model of cat allergy following systemic administration of a T cell epitope peptide (Campbell et al., J. Exp. Med 2009). In the current study we hypothesized that exposure to Der p 1 (major house dust mite [HDM] allergen)-derived peptides intranasally (local mucosal environment) could modulate markers of allergic airways disease in a murine model of HDM allergy.

Suppression of allergic airway inflammation in a mouse model of asthma by exogenous mesenchymal stem cells

Mesenchymal stem cells (MSCs) have significant immunomodulatory effects in the development of acute lung inflammation and fibrosis. However, it is still unclear as to whether MSCs could attenuate allergic airway inflammation in a mouse model of asthma. We firstly investigated whether exogenous MSCs can relocate to lung tissues in asthmatic mice and analyzed the chemotactic mechanism. Then, we evaluated the in vivo immunomodulatory effect of exogenous MSCs in asthma. MSCs (2 × 10(6)) were administered through the tail vein to mice one day before the first airway challenge. Migration of MSCs was evaluated by flow cytometry. The immunomodulatory effect of MSCs was evaluated by cell counting in bronchoalveolar lavage fluid (BALF), histology, mast cell degranulation, airway hyperreactivity and cytokine profile in BALF. Exogenous MSCs can migrate to sites of inflammation in asthmatic mice through a stromal cell-derived factor-1α/CXCR4-dependent mechanism. MSCs can protect mice against a range of allergic airway inflammatory pathologies, including the infiltration of inflammatory cells, mast cell degranulation and airway hyperreactivity partly via shifting to a T-helper 1 (Th1) from a Th2 immune response to allergens. So, immunotherapy based on MSCs may be a feasible, efficient therapy for asthma.

Bacterial-induced protection against allergic inflammation through a multicomponent immunoregulatory mechanism

BackgroundAirborne microbial products have been reported to promote immune responses that suppress asthma, yet how these beneficial effects take place remains controversial and poorly understood.MethodsWe exposed mice to the bacterium...

Suppression of allergic airway inflammation in a mouse model by Der p2 recombined BCG

Allergic asthma is a chronic inflammatory disease mediated by T helper (Th)2 cell immune responses. Currently, immunotherapies based on both immune deviation and immune suppression, including the development of recombinant mycobacteria as immunoregulatory vaccines, are attractive treatment strategies for asthma. In our previous studies, we created a genetically recombinant form of bacille Calmette-Guerin (rBCG) that expressed Der p2 of house dust mites and established that it induced a shift from a Th2 response to a Th1 response in naive mice. However, it is unclear whether rBCG could suppress allergic airway inflammation in a mouse model. In this article we report that rBCG dramatically inhibited airway inflammation, eosinophilia, mucus production and mast cell degranulation in allergic mice. Analysis of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels in bronchoalveolar lavage fluid (BALF) and lung tissue revealed that the suppression was associated with a shift from a Th2 response to a Th1 response. At the same time, rBCG induced a CD4(+) CD25(+) Foxp3(+) T-cell subtype that could suppress the proliferation of Th2 effector cells in vitro in an antigen-specific manner. Moreover, suppression of CD4(+) CD25(+) T cells could be adoptively transferred. Thus, our results demonstrate that rBCG induces both generic and specific immune responses. The generic immune response is associated with a shift from a Th2 to a Th1 cytokine response, whereas the specific immune response against Der p2 appears to be related to the expansion of transforming growth factor-beta (TGF-beta)-producing CD4(+) CD25(+) Foxp3(+) regulatory T cells. rBCG can suppress asthmatic airway inflammation through both immune deviation and immune suppression and may be a feasible, efficient immunotherapy for asthma.

Suppression of allergic airway inflammation and IgE responses by a class I restricted allergen peptide vaccine

CD8 T cells are known to deviate CD4 T-cell responses from Th2 toward Th1. Reduction of Th2 cytokines and increased interferon-γ ameliorates allergic airway disease. We have developed a novel approach to the suppression of allergic airway inflammation, by designing a MHC class I-restricted allergen peptide vaccine, which induces potent and long-lived CD8 T-cell responses. Vaccination of C57BL/6 mice before allergen sensitization completely prevented allergen-specific immunoglobulin E (IgE) antibody responses. Vaccination after sensitization failed to suppress IgE, but inhibited accumulation of eosinophils and neutrophils in airways after subsequent allergen challenge. Vaccination suppressed Th2 airway infiltration and enhanced the lung Th1 response without inducing excessive CD8 cellular infiltration or interleukin-17, and the combination of class I peptide with adjuvant was more effective than adjuvant alone. Airway hyperreactivity was prevented by vaccination in an allergen-specific fashion. Class I peptide vaccines might therefore represent a robust and long-lasting immunotherapeutic strategy in allergic disease.

Retraction: T‐bet expression by dendritic cells is required for the repolarization of allergic airway inflammation

By cross-linking B7-DC on dendritic cells (DC) the human IgM antibody (B7-DC XAb) shifts polarized immune responses from Th2 to Th1 in an antigen-specific manner. The molecular determinants governing the ability of DC to reprogram the polarity of T cell recall responses are not yet known. In addition to the expected role of T-bet expressed by T cells in regulating Th1 responses, we find using in vitro assays and an established in vivo model of allergic airway inflammation that T-bet expression by DC is also required for the polarity shift promoted by B7-DC XAb. T-bet expression by both T cells and DC is critically important for B7-DC XAb-induced down-regulation of IL-4, up-regulation of IFN-gamma and suppression of allergic airway inflammation. Moreover, retroviral reconstitution of T-bet expression in T-bet-deficient DC rescued their ability to modulate both naive and memory T-cell responses from Th2 to Th1. Our observations further our understanding of the critical mediators controlling the ability of DC to modify the responses of previously activated T cells and reveal the interesting use of the same transcription factor to regulate the inductive phenotype of DC and the inducible phenotype of T cells.