Vitamin D induces a diverse range of biological effects, including important functions in bone health, calcium homeostasis and, more recently, on immune function. The role of vitamin D during infection is of particular interest given data from epidemiological studies suggesting that vitamin D deficiency is associated with an increased risk of infection. Vitamin D has diverse immunomodulatory functions, although its role during bacterial infection remains unclear. In this study, we examined the effects of 1,25(OH)2D3, the active metabolite of vitamin D, on peripheral blood mononuclear cells (PBMCs) and purified immune cell subsets isolated from healthy adults following stimulation with the bacterial ligands heat-killed pneumococcal serotype 19F (HK19F) and lipopolysaccharide (LPS). We found that 1,25(OH)2D3 significantly reduced pro-inflammatory cytokines TNF-α, IFN-γ, and IL-1β as well as the chemokine IL-8 for both ligands (three- to 53-fold), while anti-inflammatory IL-10 was increased (two-fold, p = 0.016) in HK19F-stimulated monocytes. Levels of HK19F-specific IFN-γ were significantly higher (11.7-fold, p = 0.038) in vitamin D-insufficient adults (<50 nmol/L) compared to sufficient adults (>50 nmol/L). Vitamin D also shifted the pro-inflammatory/anti-inflammatory balance towards an anti-inflammatory phenotype and increased the CD14 expression on monocytes (p = 0.008) in response to LPS but not HK19F stimulation. These results suggest that 1,25(OH)2D3 may be an important regulator of the inflammatory response and supports further in vivo and clinical studies to confirm the potential benefits of vitamin D in this context.
Common genetic variants of IL-7 receptor α (IL-7Rα) have recently been shown to affect susceptibility to multiple sclerosis (MS) and type 1 diabetes, and survival following bone marrow transplantation. Transcription of the gene produces two dominant isoforms, with or without exon 6, which code for membrane-bound or soluble IL-7Rα, respectively. The haplotypes produce different isoform ratios. We have tested IL-7Rα mRNA expression in cell subsets and in models of T cell homeostasis, activation, tolerance, and differentiation into regulatory T cell/Th1/Th2/Th17, memory, and dendritic cells (DCs) under the hypothesis that the conditions in which haplotype differences are maximal are those likely to be the basis for their association with disease pathogenesis. Maximal differences between haplotypes were found in DCs, where the ligand is mainly thymic stromal lymphopoietin (TSLP). The MS-protective haplotype produces a much lower ratio of soluble to membrane-bound receptor, and so potentially, DCs of this haplotype are more responsive to TSLP. The TSLP/IL-7Rα interaction on DCs is known to be critical for production of thymic regulatory T cells, and reduced production of these cells in MS susceptibility haplotypes may be a basis for its association with this disease. IL-7Rα mRNA expression varies greatly through cell differentiation so that it may be a useful marker for cell states. We also show that serum levels of soluble receptor are much higher for the MS susceptibility haplotype (p = 4 × 10−13). Because signaling through IL-7Rα controls T cell regulation, this haplotype difference is likely to affect the immunophenotype and disease pathogenesis.
The human immune system is a tightly regulated network that protects the host from disease. An important aspect of this is the balance between pro-inflammatory Th17 cells and anti-inflammatory T regulatory (Treg) cells in maintaining immune homeostasis. Foxp3+ Treg are critical for sustaining immune tolerance through IL-10 and transforming growth factor-β while related orphan receptor-γt+ Th17 cells promote immunopathology and auto-inflammatory diseases through the actions of IL-17A, IL-21 and IL-22. Therefore, imbalance between Treg and Th17 cells can result in serious pathology in many organs and tissues. Recently, certain IL-17-producing cells have been found to be protective against infectious disease, particularly in relation to extracellular bacteria such Streptococcus pneumoniae; a number of other novel IL-17-secreting cell populations have also been reported to protect against a variety of other pathogens. In this mini-review, the dual roles of Treg and Th17 cells are discussed in the context of autoimmunity and infections, highlighting recent advances in the field. Development of novel strategies specifically designed to target these critical immune response pathways will become increasingly important in maintenance of human health.
Streptococcus pneumoniae (pneumococcus) and respiratory syncytial virus (RSV) are the leading causes of respiratory infections amongst children <5 years of age. Co-infection with these pathogens is common during early life and often associated with increased disease severity. Epidemiological studies have shown that low levels of Vitamin D 3 (VitD 3) are associated with increased susceptibility to respiratory pathogens. However, the role of VitD 3 in the context of pneumococcal and RSV exposure are poorly understood. We found that VitD 3 significantly reduced Th17 cell expression and IL-17A and IL-22 secretion in peripheral blood mononuclear cells (PBMCs) when stimulated with a pneumococcal whole cell antigen (WCA). Levels of IFN-γ were also decreased whilst IL-10 and IL-1β were increased. Effects of VitD 3 on innate responses following RSV stimulation was limited, only reducing IL-6. VitD 3 also reduced the number of TLR2+CD14+ monocytes, whilst increasing TLR7+CD14+ monocytes and TLR4+CD56+ NK cells. In WCA-stimulated PBMCs, VitD 3 increased IL-1β levels but reduced TLR2+CD14+ monocytes. For pneumococcal WCA-RSV co-stimulation, VitD 3 only had a limited effect, mainly through increased IL-1β and RANTES as well as TLR4+CD56+ NK cells. Our results suggest that VitD 3 can modulate the inflammatory response to pneumococci but has limited effects during viral or bacterial-viral exposure. This is the first study to examine the effects of VitD 3 in the context of pneumococcal-RSV co-stimulation, with important implications on the potential role of VitD 3 in the control of excessive inflammatory responses during pneumococcal and RSV infections.
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