Respiratory Syncytial virus infection compromises asthma tolerance by recruiting interleukin-17A-producing cells via CCR6-CCL20 signaling

Asthma tolerance can be induced by breast-feeding or oral feeding with ovalbumin (OVA). Anergy or deletion of specific T cells and generation of T regulatory cells might contribute to this process. However, whether respiratory syncytial virus (RSV) infection would affect asthma tolerance is not very clear. Here, we first established asthma and oral tolerance mouse models and then analyzed airway hypersensitivity and asthma-related genes in the lung, CCR6-expressing IL-17A⁺ cells in the lungs, hilar or mesenteric lymph nodes (HLN or MLN) among control, asthmatic, tolerized, RSV infection, and RSV-infected asthmatic and tolerized groups. We also administrated CCL20 or IL-17A neutralizing antibody to RSV-infected tolerized mice to test whether RSV infection would mobilize CCR6-expressing IL-17A⁺ cells from MLN to the infected lungs. We found that tolerized mice infected with RSV developed asthma-like responses manifested by increasing airway hypersensitivity, exacerbating peribronchial inflammation, elevating lung asthma-related genes (Il17a, Mu5ac, and Gob5), accumulating CCR6-expressing IL-17A⁺ cells in the lungs and HLN with a reduction of this cell population in MLN. CCL20-CCR6 co-expression in RSV-infected tolerized MLN was reduced. Neutralization of CCL20 reduced CD3⁺CD4⁺CCR6⁺ cells in the RSV-infected tolerized HLN. Neutralization of IL-17A mitigated the compromising effects of RSV infection on asthma tolerance. Taken together, RSV infection impairs asthma tolerance by recruiting IL-17A-producing cells via CCR6-CCL20 signaling. The findings provide novel insight into exacerbation and therapeutic strategy of asthma under RSV infection.     

CCR9 signaling in dendritic cells drives the differentiation of Foxp3+ Tregs and suppresses the allergic IgE response in the gut

The chemokine receptor CCR9 and its only known ligand CCL25 play an important role in gut inflammation and autoimmune colitis. The function of CCR9-CCL25 in the migration of immune cells is well characterized. However, its role in the immune cell differentiation is mostly not known. Using dextran sodium sulfate (DSS)-induced gut inflammation model, we showed that CCR9⁺ dendritic cells (DCs) specifically CD11b⁻CD103⁺ DCs were significantly increased in the gut-associated lymphoid tissues (GALT) compared to control mice. These CCR9⁺ DCs express lower MHC II and CD86 molecules and had regulatory surface markers (FasL and latency-associated peptide, LAP) in the GALT. In the presence of CCL25, CCR9⁺ DCs promoted in vitro differentiation of Foxp3⁺ regulatory CD4⁺ T cells (Tregs). CCL25-induced differentiation of Tregs was due to intrinsic signaling in the DCs but not through CD4⁺ T cells, which was driven by the production of thymic stromal lymphopoietin (TSLP) and not IL-10. Furthermore, adoptive transfer of CCR9⁺ DCs in C57BL/6 mice promoted Tregs but reduced the Th17 cells in the GALT, and also suppressed the OVA-specific gut-allergic response. Our results suggest CCR9⁺ DCs have a regulatory function and may provide a new cellular therapeutic strategy to control gut inflammation and allergic immune reaction.     

iNKT cells with high PLZF expression are recruited into the lung via CCL21-CCR7 signaling to facilitate the development of asthma tolerance in mice

Establishment of immune tolerance is crucial to protect humans against asthma. Promyelocytic leukemia zinc finger (PLZF) is an emerging suppressor of inflammatory responses. CCL21-CCR7 signaling mediates tolerance development. However, whether PLZF and CCL21-CCR7 are required for the development of asthma tolerance is unknown. Here, we found that Zbtb16 (coding PLZF) and Ccl21 were upregulated in OVA-induced asthma tolerance (OT) lungs by RNA-seq. PLZF physically interacted with GATA3 and its expression was higher in GATA3⁺ Th2 cells and ILC2s in OT lungs. Zbtb16-knockdown in lymphocytes promoted the differentiation of CD3e⁺CD4⁺ T cells, particularly those producing IL-4 and IL-5. Moreover, iNKT cells with high expression of PLZF were recruited into the lungs via draining lymph nodes during tolerance. Blockade of CCL21-CCR7 signaling in OT mice decreased the PLZF⁺ cell population, abolished CCR7-induced PLZF⁺ iNKT recruitment to the lungs, enhanced Th2responses and exacerbated lung pathology. In OT mice, respiratory syncytial virus (RSV) infection impeded PLZF⁺ cell and CCR7⁺PLZF⁺ iNKT cellrecruitment to the lungs and increased airway resistance. Collectively, these results indicate that PLZF could interact with GATA3 and restrain differentiation of IL-4- and IL-5-producing T cells, iNKT cells with high PLZF expression are recruited to the lungs via CCL21-CCR7 signaling to facilitate the development of asthma tolerance.     

T regulatory cells and Th1/Th2 cytokines in peripheral blood from tuberculosis patients

About 10% of people infected with Mycobacterium tuberculosis develop active tuberculosis (TB), and Th1 effector cells and Th1 cytokines play key roles in controlling M. tuberculosis infection. Here, we hypothesise that this susceptibility to M. tuberculosis infection is linked to increased T regulatory (Treg) cells and Th2 cytokines in TB patients. To test this, we recruited 101 participants (71 TB patients, 12 non-TB pulmonary diseases and 18 healthy subjects) and investigated Treg cells and Th1/Th2 cytokines in peripheral blood. CD4⁺CD25⁺ T cells and CD4⁺CD25⁺FoxP3⁺ T cells significantly increased and IL-5 dramatically decreased in TB patients relative to healthy subjects. CD8⁺CD28⁻ T cells, IFN-γ, TNF-α, IL-10 and IL-4 significantly increased in patients with culture and sputum smear-positive pulmonary TB (PTB(+)) compared with healthy subjects. CD4⁺CD25⁺FoxP3⁺ and CD8⁺CD28⁻ T cells significantly decreased in PTB(+) after one month of chemotherapy. CD4⁺, CD4⁺CD25⁺ and CD8⁺CD28⁺ T cells significantly increased in extra-pulmonary TB patients after one month of chemotherapy. These findings suggest that M. tuberculosis infection induces circulating CD4⁺CD25⁺FoxP3⁺ and CD8⁺CD28⁻ T cell expansion, which may be related to the progression of M. tuberculosis infection, and that the balance between effector immune responses and suppression immune responses is essential to control M. tuberculosis infection.     

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

CCR9 + T helper (Th) cells can induce Sjögren-like symptoms in mice and both CCR9 + Th cells and their ligand CCL25 are increased in the salivary glands of primary Sjögren's syndrome (pSS) patients. Increased circulating CCR9 + Th cells are present in pSS patients. CCR9 + Th cells are hyperresponsive to IL-7, secrete high levels of IFN-γ, IL-21, IL-17 and IL-4 and potently stimulate B cells in both patients and healthy individuals. Our aim was to study co-expression of chemokine receptors on CCR9 + Th cells and whether in pSS this might differentially affect CCR9 + Th cell frequencies. Frequencies of circulating CCR9 + and CCR9- Th cells co-expressing CXCR3, CCR4, CCR6 and CCR10 were studied in pSS patients and healthy controls. CCL25, CXCL10, CCL17, CCL20 and CCL27 mRNA and protein expression of salivary gland tissue of pSS and non-Sjögren's sicca (non-SS) patients was assessed. Chemotaxis assays were performed to study migration induced by CXCL10 and CCL25. Higher expression of CXCR3, CCR4 and CCR6 but not CCR10 was observed on CCR9 + Th cells as compared to cells lacking CCR9. Decreased frequencies of circulating memory CCR9 + CXCR3+ Th cells were found in pSS patients, which was most pronounced in the effector memory subset. Increased salivary gland CCL25 and CXCL10 expression significantly correlated and both ligands functioned synergistically based on in vitro induced chemotaxis. Decreased memory CXCR3 + CCR9+ Th cells in blood of pSS patients may be due to a concerted action of overexpressed ligands at the site of inflammation in the salivary glands facilitating their preferential migration and positioning in the lymphocytic infiltrates.     

Th22 cells are efficiently recruited in the gut by CCL28 as an alternative to CCL20 but do not compensate for the loss of Th17 cells in treated HIV-1-infected individuals

Gut CD4⁺ T cells are incompletely restored in most HIV-1-infected individuals on antiretroviral therapy, notably Th17 cells, a key subset in mucosal homeostasis. By contrast, gut Th22 cells are usually restored at normal frequencies. Th22 cells display a CCR6⁺CCR10⁺ phenotype and could thus respond to CCL20- and CCL28-mediated chemotaxis, while Th17 cells, which express CCR6 but not CCR10, depend on CCL20. Herein, we found that CCL28 is normally expressed by duodenal enterocytes of treated HIV-1-infected individuals, while CCL20 expression is blunted. Ex vivo, we showed that Th22 cells contribute to the reduction of CCL20 production by enterocytes through an IL-22- and IL-18-dependent mechanism. Th22 cells preferentially migrate via CCL20- rather than CCL28-mediated chemotaxis when both chemokines are available in the microenvironment. However, when the CCL20/CCL28 ratio drops, as in treated HIV-1-infected individuals, Th22 cells can migrate via the CCR10–CCL28 axis, as an alternative to CCR6–CCL20. This could explain the better reconstitution of gut Th22 compared with Th17 cells on antiretroviral therapy. Lastly, we assessed the relationships between the frequencies of gut Th17 and Th22 cells and inflammatory markers related to microbial translocation, and showed that Th22 cells do not compensate for the loss of Th17 cells in treated HIV-1-infected individuals.     

CCR6− regulatory T cells blunt the restoration of gut Th17 cells along the CCR6–CCL20 axis in treated HIV-1-infected individuals

The gut CD4⁺ T cells, particularly the T helper type 17 (Th17) subset, are not completely restored in most HIV-1-infected individuals despite combined antiretroviral therapy, when initiated at the chronic phase of infection. We show here that the CCR6–CCL20 chemotactic axis is altered, with reduced CCL20 production by small intestine epithelial cells in treated HIV-1-infected individuals. This leads to impaired CCR6⁺CD4⁺ T-cell homing, particularly Th17 cells, to the small intestine mucosa. In contrast, the frequency of gut FoxP3⁺ T regulatory (Treg) cells, specifically the CCR6⁻ subset, was increased. The resulting imbalance in the Th17/CCR6⁻ Treg ratio and the associated shift from interleukin (IL)-17 to IL-10 and transforming growth factor-β (TGF-β) blunts CCL20 production by enterocytes, perpetuating a negative feedback for the recruitment of CCR6⁺CD4⁺ T cells to the small intestine in treated HIV-1-infected individuals.     

Innate immunity in myasthenia gravis thymus: Pathogenic effects of Toll-like receptor 4 signaling on autoimmunity

The thymus is the main site of immune sensitization to AChR in myasthenia gravis (MG). In our previous studies we demonstrated that Toll-like receptor (TLR) 4 is over-expressed in MG thymuses, suggesting its involvement in altering the thymic microenvironment and favoring autosensitization and autoimmunity maintenance processes, via an effect on local chemokine/cytokine network. Here, we investigated whether TLR4 signaling may favor abnormal cell recruitment in MG thymus via CCL17 and CCL22, two chemokines known to dictate immune cell trafficking in inflamed organs by binding CCR4. We also investigated whether TLR4 activation may contribute to immunodysregulation, via the production of Th17-related cytokines, known to alter effector T cell (Teff)/regulatory T cell (Treg) balance. We found that CCL17, CCL22 and CCR4 were expressed at higher levels in MG compared to normal thymuses. The two chemokines were mainly detected around medullary Hassall's corpuscles (HCs), co-localizing with TLR4⁺ thymic epithelial cells (TECs) and CCR4⁺ dendritic cells (DCs), that were present in higher number in MG thymuses compared to controls. TLR4 stimulation in MG TECs increased CCL17 and CCL22 expression and induced the production of Th17-related cytokines. Then, to study the effect of TLR4-stimulated TECs on immune cell interactions and Teff activation, we generated an in-vitro imaging model by co-culturing CD4⁺ Th1/Th17 AChR-specific T cells, naïve CD4⁺CD25⁺ Tregs, DCs and TECs from Lewis rats. We observed that TLR4 stimulation led to a more pronounced Teff activatory status, suggesting that TLR4 signaling in MG thymic milieu may affect cell-to-cell interactions, favoring autoreactive T-cell activation. Altogether our findings suggest a role for TLR4 signaling in driving DC recruitment in MG thymus via CCL17 and CCL22, and in generating an inflammatory response that might compromise Treg function, favoring autoreactive T-cell pathogenic responses.     

CD8+ T cells and not CD4+ T cells are hyporesponsive to CD28- and CD40L-mediated activation in HIV-infected subjects

T cell dysfunction in HIV-infected subjects could be the consequence of altered sensitivity of CD4⁺ or CD8⁺ T cells to various costimulatory signals. Therefore, we studied proliferation and cytokine production in highly purified CD8⁺ and CD4⁺ T cells from HIV-infected and HIV⁻ subjects, induced by co-activation via cell-bound CD80, CD86 and CD40 or by allo-activation. Regardless of the nature of the first and the costimulatory signal, CD8⁺ T cells from patients proliferated consistently less than controls, while responses from CD4⁺ T cells were similar in patients and controls. This phenomenon was observed after ligation of CD28 combined with anti-CD3 or phorbol myristate acetate (PMA), but also after allogeneic stimulation and after activation by CD40 and anti-CD3. Anti-CD3 combined with CD80 or CD86 induced a mixed Th1/Th2-type cytokine profile in both CD4⁺ and CD8⁺ T cells from controls, whereas anti-CD3 plus CD40 induced only low levels of Th2-type cytokines and no interferon-gamma (IFN-γ) in CD4⁺ T cells. Compared with controls, CD4⁺ T cells from patients produced slightly lower levels of IL-10 but equal amounts of IFN-γ, IL-4 and IL-5, while CD8⁺ T cells from patients produced less of all cytokines tested. In conclusion, responses of purified CD4⁺ T cells from HIV⁺ subjects to various costimulatory pathways are relatively intact, whereas CD8⁺ T cells are hyporesponsive at the level of proliferation and cytokine production. A generalized intrinsic CD8⁺ T cell failure might contribute to viral and neoplastic complications of HIV infection.     

Pleural Mesothelial Cells Promote Expansion of IL-17–Producing CD8+ T Cells in Tuberculous Pleural Effusion

IL-17–producing CD8⁺ T lymphocytes (Tc17 cells) have recently been detected in many cancers and autoimmune diseases. However, the possible implication of Tc17 cells in tuberculous pleural effusion remains unclarified. In this study, distribution and phenotypic features of Tc17 cells in both tuberculous pleural effusion (TPE) and peripheral blood from patients with tuberculosis were determined. The effects of proinflammatory cytokines and local accessory cells (pleural mesothelial cells) on Tc17 cell expansion were also explored. We found that TPE contained more Tc17 cells than the blood. Compared with IFN-γ–producing CD8⁺ T cells, Tc17 cells displayed higher expression of chemokine receptors (CCRs) and lower expression of cytotoxic molecules. In particularly, Tc17 cells in TPE exhibited high expression levels of CCR6, which could migrate in response to CCL20. Furthermore, IL-1β, IL-6, IL-23, or their various combinations could promote Tc17 cell expansion from CD8⁺ T cells, whereas the proliferative response of Tc17 cells to above cytokines was lower than that of Th17 cells. Pleural mesothelial cells (PMCs) were able to stimulate Tc17 cell expansion via cell contact in an IL-1β/IL-6/IL-23 independent fashion. Thus this study demonstrates that Tc17 cells marks a subset of non-cytotoxic, CCR6⁺ CD8⁺ T lymphocytes with low proliferative capacity. The overrepresentation of Tc17 cells in TPE may be due to Tc17 cell expansion stimulated by pleural proinflammatory cytokines and to recruitment of Tc17 cells from peripheral blood. Additionally, PMCs may promote the production of IL-17 by CD8⁺ T cells at sites of TPE via cell–cell interactions.     

IFN-γ is essential for the inhibition of B16BL6 melanoma lung metastasis in chronic alcohol drinking mice

We previously found that chronic alcohol consumption (20% w/v in drinking water) that models the level consumed by human alcoholics, when administered to female C57BL/6 mice inhibits B16BL6 melanoma metastasis to the lung; however, the mechanism is not known. Chronic alcohol consumption increases IFN-γ producing NK, NKT, CD4⁺, and CD8⁺ T cells. To examine the impact of IFN-γ on metastasis, we inoculated B16BL6 melanoma cells i.v. into control and chronic alcohol drinking IFN-γ knockout (KO) mice. Knockout of the ifn-γ gene abrogated the anti-metastatic effects associated with alcohol consumption. We examined metastasis in common gamma-chain (γC) KO mice, which are deficient in NK, NKT and CD8⁺ T cells, and in Vα14Jα281^−/− KO mice, which are deficient in invariant NKT (iNKT) cells, in order to assess the importance of specific IFN-γ producing cell types to this effect. We found that the antimetastatic effect of alcohol was still present in γC KO mice and also in γC KO mice depleted of Gr-1⁺ cells. Knockout of iNKT cells reduced the degree but not the antimetastatic effect associated with alcohol. These results indicate that the antimetastatic effect induced by chronic alcohol consumption is IFN-γ dependent and that multiple IFN-γ producing cell types contribute to this effect.     

Interferon-gamma negatively regulates Th17-mediated immunopathology during mouse hepatitis virus infection

Fulminant hepatitis can cause acute liver failure and death in both humans and mice. However, the cellular and molecular mechanisms underlying the acute disease are still not well understood. Here, we examine the role of Th17 response in the development of the acute hepatitis following infection with mouse hepatitis virus (MHV). We show that IL-17 levels in serum are rapidly elevated and positively correlated to liver damage and death of the mice. In IFN-γR^−/− mice, Th17 response is enhanced and the elevated IL-17 production contributes to severe liver damage as well as detrimental inflammation because neutralization of IL-17 effectively suppresses inflammation and protects mice from liver injury. We further show that IFN-γ facilitates antigen-induced apoptosis of Th17 cells and adoptive transferred IFN-γR^−/−, but not IFN-γR^+/+; CD4⁺ T cells promotes an enhanced liver damage in wild-type mice. The results demonstrate an essential role of Th17 cells in MHV-induced immunopathology and the importance of IFN-γ in maintaining immune balance between Th1 and Th17 responses during acute viral infection.     

CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes

The integrin CD103 and the chemokine receptor CCR9 are co‐expressed on small intestinal CD8⁺ intraepithelial lymphocytes (IEL), naïve murine CD8⁺ T cells and by a small population of effector/memory CD8⁺ T cells, indicating a potential role for CCR9 in regulating CD103 expression and function. Here, we demonstrate that CD103, in contrast to CCR9, is down‐regulated on CD8⁺ T cells following their activation in mesenteric lymph nodes and that effector CD8⁺ T cells upon initial entry into the small intestinal epithelium are CCR9⁺CD103^–. CD103 was rapidly induced on wild‐type CD8⁺ T cells subsequent to their entry into the small intestinal epithelium, however, CCR9^–/– CD8⁺ T cells exhibited a significant delay in CD103 induction at this site. In addition, the CCR9 ligand, CCL25, that is constitutively expressed in the small intestinal epithelium, induced transient, dose‐dependent and pertussis toxin‐sensitive CD103‐mediated adhesion of CD8⁺ small intestinal IEL to a murine E‐cadherin human Fc (mEFc) fusion protein. Together, these results demonstrate a role for CCR9/CCL25 in promoting the induction and function of CD103 on CD8⁺ IEL and suggest that this chemokine receptor/chemokine pair may function to regulate lymphocyte‐epithelial interactions in the small intestinal mucosa.     

Interleukin 12 and innate molecules for enhanced mucosal immunity

Recent strategies for understanding the mechanisms underlying mucosal immune responses and subsequent development of mucosal vaccines for induction of targeted immunity now include cytokines and molecules of innate immunity. These studies have shown that cytokines influencing the development of T helper (Th) cells differentially affect the outcome of mucosal vs systemic immune responses to mucosal vaccines. Serum antigen-specific antibody (Ab) responses were enhanced when either IL-6 or IL-12 was mucosally administered with a protein antigen, while only IL-12 induced antigen-specific mucosal IgA Ab responses. Mucosal IL-6 and IL-12 also affected the type of Th cell responses induced by CD4⁺ T cells from mice that received IL-12 secreted larger amounts of IFN-γ and IL-6 when compared with mice nasally treated with IL-6. Discrepancies in the ability to enhance mucosal or systemic immune responses were also observed when human neutrophil peptide (HNP) defensins or lymphotactin were nasally coadministered with protein antigens. Only lymphotactin promoted mucosal secretory IgA (S-IgA) Ab responses while both lymphotactin and defensins enhanced systemic immunity to mucosally co-administered protein antigens. Mixed antigen-specific Th1-and Th2-type CD4⁺ T cell responses were induced in the systemic compartment by both lymphotactin and the mixture of HNP-1, HNP-2, and HNP-3 defensins. However, HNPs failed to significantly enhance cytokine secretion by mucosally derived, antigen-specific CD4⁺ T cells relative to those isolated from the systemic compartment. In summary, these studies clearly show that IL-12 and lymphotactin are able to trigger S-IgA Ab responses and provide new avenues for the design of safe and targeted mucosal vaccines.     

Cytokine expression in CD4+ cells exposed to the monocyte locomotion inhibitory factor produced by Entamoeba histolytica

Entamoeba histolytica produces monocyte locomotion inhibitory factor (MLIF), a pentapeptide with in vitro and in vivo anti-inflammatory properties. MLIF may interfere with leukocyte migration, disturbing the balance of pro- and anti-inflammatory cytokines secreted by CD4⁺ T lymphocytes. We evaluated the effect of MLIF on expression of pro- and anti-inflammatory cytokines in human CD4⁺ T lymphocytes. Regulatory cytokines [interleukin-1 beta (IL-1β), IL-2, interferon gamma (IFN-γ), IL-5, IL-6, and IL-10] were studied by enzyme-linked immunosorbent assay method in CD4⁺-cell supernatant fluids. Proinflammatory cytokines were produced per se by MLIF (IL-1β, IL-2, and IFN-γ) and also anti-inflammatory cytokines (IL-5, IL-6, and IL-10) with 1-phorbol-12 myristate-13 acetate + MLIF; the IL-1β, IFN-γ, IL-5 and IL-6 production was inhibited but not that of IL-10 which disclosed increase in its expression. MLIF disturbs the pro- and anti-inflammatory balance, and it induces inhibition of IL-1β (principal proinflammatory cytokine) and increases IL-10 (prototype of an anti-inflammatory cytokine).     

Cytokines and chemoattractants in allergic inflammation

It is now generally accepted type 2 T helper (Th2) cytokines and some chemoattractants play an essential role in the pathogenesis of the allergic inflammation. The effects of Th2 cytokines, such as interleukin (IL)-4, IL-5, IL-9, and IL-13, account for virtually all the pathophysiological manifestations of allergy and asthma. Moreover, both Th2 cells and the effector cells usually present in the areas of allergic inflammation (basophils, mast cells, and eosinophils) express chemoattractant receptors, such as CCR3, CCR4, CCR8 and CRTH2. Therefore, interactions of eotaxin(s), eotaxin/CCL11, RANTES/CCL5, and MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13 with CCR3 are responsible for the recruitment of basophils, eosinophils and mast cells, whereas interactions of CCR4 with MDC/CCL22 or TARC/CCL17, CCR8 with I-309/CCL1, and CRTH2 with prostaglandin D(2) play a critical role in the allergen-induced recruitment of Th2 cells in the target tissues of allergic inflammation. The demonstration that Th2-polarized responses against allergens represent the triggering event for the development of allergic diseases, together with the recognition that some chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation, can provide the conceptual basis for the development of new therapeutic strategies in allergic conditions.     

IL-25 Promotes Th2 Immunity Responses in Airway Inflammation of Asthmatic Mice via Activation of Dendritic Cells

Allergic asthma occurs as a consequence of inappropriate immunologic inflammation to allergens and characterized by Th2 adaptive immune response. Recent studies indicated that interleukin (IL)-25, a member of the IL-17 cytokine family, had been implicated in inducing Th2 cell-dependent inflammation in airway epithelium and IL-25-deficient mice exhibit impaired Th2 immunity responses; however, how these cytokines influence innate immune responses remains poorly understood. In this study, we used ovalbumin (OVA) sensitization and challenge to induce the murine asthmatic model and confirmed by histological analysis of lung tissues and serum levels of total and OVA-specific immunoglobulin (Ig)-E. The expression of IL-25 was detected by quantitative real-time PCR and immunohistochemistry, respectively, and the dendritic cells (DCs) activation was detected by levels of CD80 and CD86 in bronchoalveolar lavage fluid (BALF) by flow cytometry. The mice sensitized and challenged with OVA showed high expression of IL-25 in both mRNA and protein levels in lungs. We detected the expression of CD80 and CD86 in BALF was also increased. A tight correlation between IL-25 mRNA and other Th2 cells producing cytokines such as IL-4, IL-5, and IL-13 in BALF was identified. Furthermore, when the asthmatic mice were treated with inhaled corticosteroids, the inflammatory cells infiltration and the inflammatory cytokines secretion were significantly decreased. In this study, we show that IL-25 promoted the accumulation of co-stimulatory molecules of CD80 and CD86 on DCs and then induced the differentiation of prime naive CD4⁺ T cells to become proinflammatory Th2 cells and promoted Th2 cytokine responses in OVA-induced airway inflammation. The ability of IL-25 to promote the activation and differentiation of DCs population was identified as a link between the IL-17 cytokine family and the innate immune response and suggested a previously unrecognized innate immune pathway that promotes Th2 cytokine responses in asthmatic airway inflammation. Inhaled corticosteroids might be capable of inhibiting the promotion of IL-25 and present a promising strategy for the treatment of asthma