AUTHOR=Chen Yin-Huai , Cheadle Charlotte E. , Rice Louise V. , Pfeffer Paul E. , Dimeloe Sarah , Gupta Atul , Bush Andrew , Gooptu Bibek , Hawrylowicz Catherine M. 

TITLE=The Induction of Alpha-1 Antitrypsin by Vitamin D in Human T Cells Is TGF-β Dependent: A Proposed Anti-inflammatory Role in Airway Disease

JOURNAL=Frontiers in Nutrition

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2021.667203

DOI=10.3389/fnut.2021.667203

ISSN=2296-861X

ABSTRACT=<p><bold>Background:</bold> 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)<sub>2</sub>D3) treatment induced alpha-1 antitrypsin (AAT) expression in CD4+, but not CD8+ T cells, with evidence supporting an immunoregulatory role.</p><p><bold>Research Question:</bold> 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)<sub>2</sub>D3-induced upregulation of AAT by vitamin D in CD8+ T cells <italic>in vitro</italic> and correlated circulating vitamin D levels with lung AAT levels <italic>in vivo</italic>.</p><p><bold>Results:</bold> 1,25(OH)<sub>2</sub>D3 in combination with TGF-β1 increased AAT expression by CD8+ T cells, as well as <italic>VDR</italic> and <italic>RXR</italic>α 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)<sub>2</sub>D3 was associated with increased TGF-β bioactivity and neutralisation of TGF-β partially abrogated 1,25(OH)<sub>2</sub>D3-induced <italic>SERPINA1</italic> gene expression. Neither CD4+ nor CD8+ T cells responded to the circulating vitamin D precursor, 25-hydroxyvitamin D3 for induction of <italic>SERPINA1</italic>, suggesting that local generation of 1,25(OH)<sub>2</sub>D3 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)<sub>2</sub>D3. 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)<sub>2</sub>D3-induced AAT. However, CD8+ T cells from adults with AAT-deficiency, homozygous for the Z allele of <italic>SERPINA1</italic>, were unable to mount this response. AAT levels in the airways of children with asthma and controls correlated with circulating 25(OH)D3.</p><p><bold>Conclusions:</bold> 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 <italic>SERPINA1</italic> 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.</p>