Development of Allergic Inflammation in a Murine Model of Asthma Is Dependent on the Costimulatory Receptor Ox40

Asthma is thought to result from an abnormal expansion of CD4 T cells reactive with airborne allergens, and pathology is controlled by several cytokines of the T helper type 2 (Th2) family. The exact molecules which are involved in generating allergen-reactive T cells are not clear. Studies with blocking reagents or knockout animals have shown that the CD28/B7 interaction partially controls development of allergic asthma in mouse models, but may not be the sole molecule involved. In this report, we have investigated the role of the tumor necrosis factor receptor family member OX40 in allergic inflammation using OX40-deficient mice. OX40 has been shown to participate in regulating clonal expansion and memory development of CD4 T cells and may synergize with CD28. Our studies demonstrate that OX40−/− mice, primed with the model allergen ovalbumin and challenged through the airways with aerosolized antigen, are severely impaired in their ability to generate a Th2 response characterized by high levels of interleukin (IL)-5, IL-4, and immunoglobulin E. Moreover, OX40−/− mice exhibit diminished lung inflammation, including an 80–90% reduction in eosinophilia and mucus production, less goblet cell hyperplasia, and significantly attenuated airway hyperreactivity. These studies highlight the potential importance of OX40 in development of allergic asthma and suggest that targeting OX40 may prove useful therapeutically.

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SERPINB10 contributes to asthma by inhibiting the apoptosis of allergenic Th2 cells

Respiratory Research ◽

10.1186/s12931-021-01757-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuqing Mo ◽

Ling Ye ◽

Hui Cai ◽

Guiping Zhu ◽

Jian Wang ◽

...

Keyword(s):

T Cells ◽

Allergic Asthma ◽

Cd4 T Cells ◽

Quantitative Polymerase Chain Reaction ◽

Allergic Inflammation ◽

Specific Ige ◽

Th2 Cells ◽

Th1 Cells ◽

Th2 Response ◽

Th1 And Th2

Abstract Background Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 2 (Th2) response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells. Methods Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in human CD4 T cells with lentivirus. Results Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells. Conclusion Our results suggest that SERPINB10 may contribute to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

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SERPINB10 Contributes to Asthma by Inhibiting the Apoptosis of Allergenic Th2 Cells

10.21203/rs.3.rs-135747/v1 ◽

2020 ◽

Author(s):

Yuqing Mo ◽

Ling Ye ◽

Hui Cai ◽

Guiping Zhu ◽

Jian Wang ◽

...

Keyword(s):

T Cells ◽

Allergic Asthma ◽

Cd4 T Cells ◽

Quantitative Polymerase Chain Reaction ◽

Allergic Inflammation ◽

Specific Ige ◽

Th2 Cells ◽

Th1 Cells ◽

Th2 Response ◽

Th1 And Th2

Abstract Background: Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 1 (Th1) /Th2 response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells.Methods: Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in CD4 T cells with lentivirus. Results: Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells.Conclusion: Our results suggest that SERPINB10 may contributes to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

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Nonredundant Roles for CD1d-restricted Natural Killer T Cells and Conventional CD4+ T Cells in the Induction of Immunoglobulin E Antibodies in Response to Interleukin 18 Treatment of Mice

Journal of Experimental Medicine ◽

10.1084/jem.20021701 ◽

2003 ◽

Vol 197 (8) ◽

pp. 997-1005 ◽

Cited By ~ 76

Author(s):

Tomohiro Yoshimoto ◽

Booki Min ◽

Takaaki Sugimoto ◽

Nobuki Hayashi ◽

Yuriko Ishikawa ◽

...

Keyword(s):

T Cells ◽

Natural Killer ◽

Cd4 T Cells ◽

Immunoglobulin E ◽

Allergic Inflammation ◽

Cd40 Ligand ◽

Nkt Cells ◽

Class Ii ◽

Natural Killer T

Interleukin (IL)-18 synergizes with IL-12 to promote T helper cell (Th)1 responses. Somewhat paradoxically, IL-18 administration alone strongly induces immunoglobulin (Ig)E production and allergic inflammation, indicating a role for IL-18 in the generation of Th2 responses. The ability of IL-18 to induce IgE is dependent on CD4+ T cells, IL-4, and signal transducer and activator of transcription (stat)6. Here, we show that IL-18 fails to induce IgE both in CD1d−/− mice that lack natural killer T (NKT) cells and in class II−/− mice that lack conventional CD4+ T cells. However, class II−/− mice reconstituted with conventional CD4+ T cells show the capacity to produce IgE in response to IL-18. NKT cells express high levels of IL-18 receptor (R)α chain and produce significant amounts of IL-4, IL-9, and IL-13, and induce CD40 ligand expression in response to IL-2 and IL-18 stimulation in vitro. In contrast, conventional CD4+ T cells express low levels of IL-18Rα and poorly respond to IL-2 and IL-18. Nevertheless, conventional CD4+ T cells are essential for B cell IgE responses after the administration of IL-18. These findings indicate that NKT cells might be the major source of IL-4 in response to IL-18 administration and that conventional CD4+ T cells demonstrate their helper function in the presence of NKT cells.

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Assessment of Allergen-Responsive Regulatory T Cells in Experimental Asthma Induced in Different Mouse Strains

Mediators of Inflammation ◽

10.1155/2021/7584483 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

C. T. Azevedo ◽

A. C. Cotias ◽

A. C. S. Arantes ◽

T. P. T. Ferreira ◽

M. A. Martins ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Allergic Asthma ◽

Treg Cell ◽

Allergen Challenge ◽

Treg Cells ◽

Airway Hyperreactivity ◽

Whole Body ◽

Mouse Strains ◽

Th2 Response

Background. Regulatory T cells (Tregs) are important in regulating responses to innocuous antigens, such as allergens, by controlling the Th2 response, a mechanism that appears to be compromised in atopic asthmatic individuals. Different isogenic mouse strains also have distinct immunological responses and susceptibility to the experimental protocols used to develop lung allergic inflammation. In this work, we investigated the differences in the frequency of Treg cell subtypes among A/J, BALB/c, and C57BL/6, under normal conditions and following induction of allergic asthma with ovalbumin (OVA). Methods. Subcutaneous sensitization followed by 4 consecutive intranasal OVA challenges induced asthma characteristic changes such as airway hyperreactivity, inflammation, and production of Th2 cytokines (IL-4, IL-13, IL-5, and IL-33) in the lungs of only A/J and BALB/c but not C57BL/6 strain and evaluated by invasive whole-body plethysmography, flow cytometry, and ELISA, respectively. Results. A/J strain naturally showed a higher frequency of CD4+IL-10+ T cells in the lungs of naïve mice compared to the other strains, accompanied by higher frequencies of CD4+IL-4+ T cells. C57BL/6 mice did not develop lung inflammation and presented higher frequency of CD4+CD25+Foxp3+ Treg cells in the bronchoalveolar lavage fluid (BALF) after the allergen challenge. In in vitro settings, allergen-specific stimulation of mediastinal LN (mLN) cells from OVA-challenged animals induced higher frequency of CD4+IL-10+ Treg cells from A/J strain and CD4+CD25+Foxp3+ from C57BL/6. Conclusions. The observed differences in the frequencies of Treg cell subtypes associated with the susceptibility of the animals to experimental asthma suggest that CD4+CD25+Foxp3+ and IL-10-producing CD4+ Treg cells may play different roles in asthma control. Similar to asthmatic individuals, the lack of an efficient regulatory response and susceptibility to the development of experimental asthma in A/J mice further suggests that this strain could be preferably chosen in experimental models of allergic asthma.

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The Notch mediator RBP-J in CD4 T cells plays a crucial role in the induction of allergic asthma in mice

Pneumologie ◽

10.1055/s-0032-1329794 ◽

2012 ◽

Vol 66 (11) ◽

Author(s):

R Hendriks ◽

A KleinJan ◽

M De Bruijn ◽

M Van Nimwegen ◽

I Bergen ◽

...

Keyword(s):

T Cells ◽

Allergic Asthma ◽

Crucial Role ◽

Cd4 T Cells

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Depletion of tumor necrosis factor receptor superfamily member 9 (TNFRSF9; 4–1BB; CD137)+/CD4 + T cells to improve adoptive cell therapy treatment of cancer

Science-Business eXchange ◽

10.1038/scibx.2012.139 ◽

2012 ◽

Vol 5 (5) ◽

pp. 139-139

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Cell Therapy ◽

Cd4 T Cells ◽

Tumor Necrosis ◽

Adoptive Cell Therapy ◽

Tumor Necrosis Factor Receptor ◽

Necrosis Factor ◽

Therapy Treatment

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Role of Superantigens in Allergic Inflammation: Their Relationship to Allergic Rhinitis, Chronic Rhinosinusitis, Asthma, and Atopic Dermatitis

American Journal of Rhinology and Allergy ◽

10.1177/1945892418801083 ◽

2018 ◽

Vol 32 (6) ◽

pp. 502-517 ◽

Cited By ~ 11

Author(s):

Nuray Bayar Muluk ◽

Fazilet Altın ◽

Cemal Cingi

Keyword(s):

T Cells ◽

Allergic Rhinitis ◽

Atopic Dermatitis ◽

Inflammatory Response ◽

Chronic Rhinosinusitis ◽

Inflammatory Responses ◽

Immunoglobulin E ◽

Severe Disease ◽

Allergic Inflammation ◽

Allergic Dermatitis

Objectives Our intention was to review all material published to date regarding superantigens (SAgs) and allergy from an otorhinolaryngological viewpoint to understand this association more clearly. Methods We identified all materials published mentioning both SAg and allergic rhinitis (AR), chronic sinusitis, asthma, and atopic dermatitis (AD) that are indexed on PubMed, Google, or the ProQuest Central databases. Results Staphylococcus aureus is a significant bacterial pathogen in humans and has the ability to produce enterotoxins with superantigenic features. The inflammatory response in allergy seen in both B cell and T cell may be attributed to SAgs. Sufferers of both allergic asthma with rhinitis and AR alone produce serological evidence of immunoglobulin E formation to SAgs produced by S. aureus. Perennial AR sufferers carry S. aureus more frequently and the presence of the organism within the nasal cavity may exacerbate perennial AR. SAg produced by S. aureus potentially worsens the asthmatic inflammatory response within the airway and may lead to the airways becoming hyperresponsive, as well as possibly activating T cells if asthmatic control is poor. Staphylococcal SAgs potentially increase the risk of developing chronic rhinosinusitis with nasal polyposis, additionally being a marker for more severe disease. If SAgs bring about chronic inflammatory responses in the nose and sinuses, then T cells excreting interferon-gamma may be a crucial mediator. In allergic dermatitis, S. aureus could be a key player in exacerbation of the condition. Even in younger pediatric patients with allergic dermatitis, allergic hypersensitivity to SAgs is frequent and may be a factor explaining how severe the condition becomes. Conclusion Just as SAgs are known to feature in many allergic conditions, they play their part in AR, chronic rhinosinusitis, asthma, and AD. Further research is required before the relationship between SAgs and allergy can be adequately explained.

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Protective effects of combined Mycobacterium bovis BCG and interleukin-12 vaccination on airway inflammation in a murine model of allergic asthma

Clinical & Investigative Medicine ◽

10.25011/cim.v33i3.13726 ◽

2010 ◽

Vol 33 (3) ◽

pp. 196 ◽

Cited By ~ 4

Author(s):

Xia Ke ◽

Jiangju Huang ◽

Quan Chen ◽

Suling Hong ◽

Daoyin Zhu

Keyword(s):

Airway Inflammation ◽

Allergic Asthma ◽

Mycobacterium Bovis ◽

Immunoglobulin E ◽

Allergic Airway Inflammation ◽

Interleukin 12 ◽

Protective Effects ◽

Th2 Response ◽

Bcg Vaccination ◽

Th2 Responses

Purpose. Allergic asthma is characterized by chronic airway inflammation and airway hyperresponsiveness driven by allergen-specific T helper (Th)2 cells. Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination has been documented to suppress Th2 responses and allergic airway inflammation in animal models. Since interleukin (IL)-12 is capable of inhibiting Th2 responses, we sought to investigate whether IL-12 could function as an adjuvant to increase the efficacy of BCG vaccination against allergic asthma. Methods. BALB/c neonatal mice (24 mice, 48-72 h old) were randomly divided into 3 subgroups (n = 8 for each group) to be immunized with PBS (control) or BCG with or without DNA plasmid-expressing IL-12. All of the mice were then sensitized and provoked with ovalbumin (OVA) to establish a model of allergic asthma. Results. Mice vaccinated with BCG alone showed a significant reduction in airway inflammation, percentage of eosinophils in bronchoalveolar lavage (BAL) fluid, and serum OVA-specific immunoglobulin E (IgE) levels in comparison with control animals. The suppressive effects of BCG were substantially augmented by the combination with IL-12. Furthermore, a decreased IL-4 and increased interferon-gamma (IFN-γ) production in BAL fluid were observed in animals inoculated with BCG alone or with IL-12 relative to control animals. Conclusion. Our data indicate that the combined vaccination with BCG and IL-12 yields a favorable outcome in prevention of experimental allergic airway inflammation, which is likely mediated through triggering a shift from a Th2 response to a Th1 response.

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Hyper Immunoglobulin E Response in Mice with Monoclonal Populations of B and T Lymphocytes1✪

Journal of Experimental Medicine ◽

10.1084/jem.194.9.1349 ◽

2001 ◽

Vol 194 (9) ◽

pp. 1349-1360 ◽

Cited By ~ 76

Author(s):

Maria A. Curotto de Lafaille ◽

Stephanie Muriglan ◽

Mary-Jean Sunshine ◽

Ying Lei ◽

Nino Kutchukhidze ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Immunoglobulin E ◽

Effector Memory ◽

Serum Ige ◽

Activation Induced Cell Death ◽

Normal Individuals ◽

Specific Effector ◽

Ige Response

A key event in the pathogenesis of allergies is the production of antibodies of the immunoglobulin (Ig)E class. In normal individuals the levels of IgE are tightly regulated, as illustrated by the low serum IgE concentration. In addition, multiple immunizations are usually required to generate detectable IgE responses in normal experimental animals. To define the parameters that regulate IgE production in vivo, we generated mice bearing monoclonal populations of B and T lymphocytes specific for influenza virus hemagglutinin (HA) and chicken ovalbumin (OVA), respectively. A single immunization of the monoclonal mice with the cross-linked OVA-HA antigen led to serum IgE levels that reached 30–200 μg/ml. This unusually high IgE response was prevented by the infusion of regulatory α/β CD4+ T cells belonging to both CD25+ and CD25− subpopulations. The regulation by the infused T cells impeded the development of fully competent OVA-specific effector/memory Th2 lymphocytes without inhibiting the initial proliferative response of T cells or promoting activation-induced cell death. Our results indicate that hyper IgE responses do not occur in normal individuals due to the presence of regulatory T cells, and imply that the induction of regulatory CD4+ T cells could be used for the prevention of atopy.

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