Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis

Kreindler, James L.; Steele, Chad; Nguyen, Nhung; Chan, Yvonne R.; Pilewski, Joseph M.; Alcorn, John F.; Vyas, Yatin M.; Aujla, Shean; Finelli, Peter; Blanchard, Megan L.; Zeigler, Steven F.; Logar, Alison J.; Hartigan, Elizabeth; Kurs‐Lasky, Marcia; Rockette, Howard E.; Ray, Anuradha; Kolls, Jay K.

doi:10.1172/jci42388

Cited by 136 publications

(129 citation statements)

References 43 publications

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“…Previous studies have characterized the T cell response in human CF patients (33,34) (24,26,27,30) (35) and murine P. aeruginosa (36)(37)(38)(39)(40) or Aspergillus fumigatus infection models (41)(42)(43), providing evidence that the adaptive T cell response in CF is altered at several levels. CF T cells were found to be prone to a Th2 phenotype, with the CFTR mutation itself and/or chronic infections with P. aeruginosa as possible underlying factors (42,(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

118

127

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Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.

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Section: Discussionmentioning

confidence: 99%

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

118

127

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“…AM: alveolar macrophage; DC: dendritic cell; TNF: tumour necrosis factor. Reproduced and modified with permission from [16]; see also [17] and [18] for detailed discussion. assumption arises from several lines of investigation.…”

Section: Antifungal Therapy In Abpa and Safsmentioning

confidence: 99%

“…The pathophysiology of ABPA results from florid T-helper cell (Th)2 innate and adaptive immune responses in susceptible hosts who are unable to efficiently clear the respiratory epithelium of inhaled fungal spores ( fig. 1) [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

Moss

2013

Eur Respir J

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Severe asthma with fungal sensitisation and allergic bronchopulmonary aspergillosis encompass two closely related subgroups of patients with severe allergic asthma. Pulmonary disease is due to pronounced host inflammatory responses to noninvasive subclinical endobronchial infection with filamentous fungi, usually Aspergillus fumigatus. These patients usually do not achieve satisfactory disease control with conventional treatment of severe asthma, i.e. high-dose inhaled corticosteroids and long-acting bronchodilators. Although prolonged systemic corticosteroids are effective, they carry a substantial toxicity profile. Supplementary or alternative therapies have primarily focused on use of antifungal agents including oral triazoles and inhaled amphotericin B. Immunomodulation with omalizumab, a humanised anti-IgE monoclonal antibody, or "pulse" monthly high-dose intravenous corticosteroid, has also been employed. This article considers the experience with these approaches, with emphasis on recent clinical trials. @ERSpublications Treatment of fungal asthma includes glucocorticoids, azoles, amphotericin and anti-IgE. Trial validation is needed.

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“…We have recently shown that the active form of vitamin D (1,25-dihydroxyvitamin D 3 ) can suppress Aspergillus fumigatusspecific Th2 responses in peripheral CD4 ϩ T cells in patients with cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis (ABPA) (10). This suppression of Th2 development was associated with an increase in transforming growth factor ␤-positive (TGF-␤ ϩ ) regulatory T cells as well as suppression of OX40L, a costimulatory molecule regulated by TSLP in vitro (7,10).…”

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confidence: 99%

Vitamin D Regulation of OX40 Ligand in Immune Responses to Aspergillus fumigatus

et al. 2013

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(1) and promoting the proliferation of distinct T helper (Th) cell subsets (2). CD11c ϩ is a transmembrane protein found on the surface of DCs. CD11c ϩ DCs are a critical DC subpopulation responsible for antigen-specific T cell activation (3). Human CD11c ϩ cells in peripheral blood express receptors for thymic stromal lymphopoietin (TSLP), an epithelial cell cytokine that can drive Th2 differentiation (4). Expression of TSLP is increased in antigeninduced allergen models (5), and Th2 responses downstream of TSLP are necessary for the development of inflammatory allergic responses (6). TSLP potently activates CD11c ϩ cells and primes naive T cells to produce the Th2 cytokines interleukin-4 (IL-4), IL-5, and IL-13 (4). Further, TSLP-activated DCs express the costimulatory molecule OX40 ligand (OX40L), which is responsible for triggering Th2 polarization (7), and blocking OX40L inhibits antigen-specific Th2 inflammation (8). Recently, it has been shown that TSLP induces OX40L in DCs through the activation of NF-B components which can bind to NF-B-like binding sites in the OX40L promoter to induce production of OX40L (9).We have recently shown that the active form of vitamin D (1,25-dihydroxyvitamin D 3 ) can suppress Aspergillus fumigatusspecific Th2 responses in peripheral CD4 ϩ T cells in patients with cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis (ABPA) (10). This suppression of Th2 development was associated with an increase in transforming growth factor ␤-positive (TGF-␤ ϩ ) regulatory T cells as well as suppression of OX40L, a costimulatory molecule regulated by TSLP in vitro (7,10). These data are consistent with prior data showing that vitamin D can decrease the maturation of DCs (11) ϩ cells, specifically, OX40L, CD80, CD86, and inducible T-cell costimulator ligand (ICOS-L). Moreover, vitamin D deficiency led to an increased Th2 response to A. fumigatus, which was attenuated with neutralization of OX40L in vivo, suggesting that OX40L is required for enhanced Th2 responses in this model. Furthermore, we show that vitamin D treatment leads to vitamin D receptor (VDR) binding to the OX40L promoter and represses OX40L promoter activity in vitro. We discovered that VDR, NF-B p50, and NF-B p65 bind to the promoter region of OX40L, which can regulate the expression of OX40L. These data demonstrate that vitamin D directly regulates the expression of OX40L, which may explain the increased immune response in vitamin D deficiency seen in Th2-mediated diseases such as ABPA. MATERIALS AND METHODS Animals.We purchased 4-to 6-week-old female BALB/c mice (from the Jackson Laboratory). Mice were housed in specific-pathogen-free rooms within animal care facilities at the Louisiana State University Health Sciences Center (LSUHSC) and the Children's Hospital of Pittsburgh of UPMC. All mouse experiments were approved by the Institutional Animal Care and Use Committee at LSUHSC and the Children's Hospital of Pittsburgh of UPMC under university-approved protocols. Mice were provided with food and water ad l...

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Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis

Abstract: Allergic bronchopulmonary aspergillosis (ABPA) is caused by a dominant

Cited by 136 publications

References 43 publications

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

Vitamin D Regulation of OX40 Ligand in Immune Responses to Aspergillus fumigatus

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