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

Abstract

(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...

Human CD141+ Dendritic Cells Induce CD4+ T Cells To Produce Type 2 Cytokines

“…In contrast, 1,25 OH-vitamin D3 substantially reduces OX40L expression while increasing expression of TGF-β in human blood CD11c + DCs and ameliorates allergic bronchopulmonary aspergillosis in cystic fibrosis patients (51). Murine study showed that the regulation of vitamin D3 on OX40L expression in DCs is mediated through alteration of NF-kB p50 binding in the OX40L promoter (52). …”

Pattern recognition pathways leading to a Th2 cytokine bias in allergic bronchopulmonary aspergillosis patients

“…We therefore investigated whether OX40L is also involved in the Th2 responses induced by Aspergillus in human PBMCs. As TNF and IL-1 can modulate the expression of OX40L [28,29], we analysed whether blocking TNF or IL-1 would result in a different expression of OX40L in PBMCs. 5d).…”

“…Although it is reported that TNF can increase OX40L expression in smooth muscle cells, significantly higher in asthmatic than non-asthmatic patients [28] and TNF can up-regulate OX40L promoter-activity [29], this mechanism appears to play a more prominent role in DC-driven Th2 responses [55].…”

“…5d). As TNF and IL-1 can modulate the expression of OX40L [28,29], we analysed whether blocking TNF or IL-1 would result in a different expression of OX40L in PBMCs. We observed no significant modulation of the Aspergillusinduced OX40L expression in the presence of Adalimumab or Anakinra (Fig.…”

Vitamin D levels in asthmatic patients with and without allergic bronchopulmonary aspergillosis

“…This Th2 response is unable to clear the fungi, however, the resultant exuberant inflammation leads to the characteristic immunological and pathological changes associated with this condition . Recently, it has been shown that peripheral CD11c+, thymic stromal lymphopoietin‐activated dendritic cells from patients with ABPA and CF induce robust Th2 cytokine responses from CD4 + T‐cells; and, in vitro treatment with vitamin D blunted these responses . Moreover, vitamin D levels have been shown to be reduced in patients with ABPA complicating CF .…”