Abstract
Background: Vitamin D upregulates anti-inflammatory and antimicrobial pathways that promote respiratory health. Vitamin D synthesis is initiated following skin exposure to sunlight, however nutritional supplementation can be required to address deficiency, for example during the winter months or due to cultural constraints. We recently reported that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment induced alpha-1 antitrypsin (AAT) expression in CD4+, but not CD8+ T cells, with evidence supporting an immunoregulatory role.Research Question: To understand the relationship between vitamin D, lung AAT levels and T lymphocytes further we investigated whether TGF-β is required as a co-factor for 1,25(OH)2D3-induced upregulation of AAT by vitamin D in CD8+ T cells in vitro and correlated circulating vitamin D levels with lung AAT levels in vivo.Results: 1,25(OH)2D3 in combination with TGF-β1 increased AAT expression by CD8+ T cells, as well as VDR and RXRα gene expression, which may partly explain the requirement for TGF-β. CD4+ T cells may also require autocrine stimulation with TGF-β as a co-factor since 1,25(OH)2D3 was associated with increased TGF-β bioactivity and neutralisation of TGF-β partially abrogated 1,25(OH)2D3-induced SERPINA1 gene expression. Neither CD4+ nor CD8+ T cells responded to the circulating vitamin D precursor, 25-hydroxyvitamin D3 for induction of SERPINA1, suggesting that local generation of 1,25(OH)2D3 is required. Transcriptional gene profiling studies previously demonstrated that human bronchial epithelial cells rapidly increased TGF-β2 gene expression in response to 1,25(OH)2D3. Here, human epithelial cells responded to precursor 25(OH)D3 to increase bioactive TGF-β synthesis. CD8+ T cells responded comparably to TGF-β1 and TGF-β2 to increase 1,25(OH)2D3-induced AAT. However, CD8+ T cells from adults with AAT-deficiency, homozygous for the Z allele of SERPINA1, were unable to mount this response. AAT levels in the airways of children with asthma and controls correlated with circulating 25(OH)D3.Conclusions: Vitamin D increases AAT expression in human T cells and this response is impaired in T cells from individuals homozygous for the Z allele of SERPINA1 in a clinic population. Furthermore, a correlation between circulating vitamin D and airway AAT is reported. We propose that vitamin D-induced AAT contributes to local immunomodulation and airway health effects previously attributed to vitamin D.
Highlights
Vitamin D is increasingly recognised as an important factor in regulating immunity and respiratory health, and vitamin D deficiency is associated with several immune-mediated airway diseases, including asthma and chronic obstructive pulmonary disease (COPD) [1,2,3]
Given the proposed role of CD8+ T cells in chronic airway conditions such as COPD [23], we investigated whether a co-factor that acts in concert with 1,25(OH)2D3 may induce Alpha-1 antitrypsin (AAT) synthesis by human CD8+ T cells
Our study demonstrates that vitamin D increases AAT synthesis in human T cells, via a TGF-dependent mechanism, a pathway that is impaired in individuals with a genetic mutation (PiZZ) that results in decreased levels of AAT secretion
Summary
Vitamin D is increasingly recognised as an important factor in regulating immunity and respiratory health, and vitamin D deficiency is associated with several immune-mediated airway diseases, including asthma and chronic obstructive pulmonary disease (COPD) [1,2,3] This is attributed to its diverse immuno-modulatory functions including the capacity to promote anti-microbial pathways, suppress inflammatory responses while enhancing immuno-modulatory functions such as anti-inflammatory IL-10 production [4, 5]. Alpha-1 antitrypsin (AAT) plays a critical role in protecting lung parenchymal tissue from direct elastinolytic degradation and pro-inflammatory effects of serine proteases, notably neutrophil elastase [6] It is predominantly synthesized in the liver by hepatocytes and is secreted into the plasma as the most abundant circulating antiprotease. Research Question: To understand the relationship between vitamin D, lung AAT levels and T lymphocytes further we investigated whether TGF-β is required as a co-factor for 1,25(OH)2D3-induced upregulation of AAT by vitamin D in CD8+ T cells in vitro and correlated circulating vitamin D levels with lung AAT levels in vivo
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