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

TY - JOUR

T1 - 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

AU - Hawrylowicz, Catherine M.

AU - Chen, Yin-Huai

AU - Cheadle, Charlotte E.

AU - Rice, Louise V.

AU - Pfeffer, Paul E.

AU - Dimeloe, Sarah

AU - Gupta, Atul

AU - Bush, Andrew

N1 - Funding Information: CC, LR, and SD were all MRC-funded Ph.D. students through the MRC and Asthma UK Centre for Allergic Mechanisms in Asthma (G1000758). Y-HC, LR, and CC with CH were further supported through Pilot and Feasibility grants from the Alpha 1 Foundation. This research also received support from the National Institute for Health Research (NIHR) Clinical Research Facility at Guy’s & St Thomas’ NHS Foundation Trust and NIHR Funding Information: We wish to dedicate this paper to our colleague and co-author, LR, who sadly passed away in November 2019. She is greatly missed as both a loyal colleague and friend and as a gifted scientist of great integrity. We thank the families and blood donors for participation in this study. We thank Professor Daniel Rifkin, New York University, for sharing mink lung epithelial cell lines (MLECs). We thank Professor Sejal Saglani, Imperial College London and Professor John Hurst and his colleagues, Royal Free Hospital London, London Alpha-1 Antitrypsin Deficiency Service, for facilitating studies with paediatric and AAT-deficient patients, respectively. Funding. CC, LR, and SD were all MRC-funded Ph.D. students through the MRC and Asthma UK Centre for Allergic Mechanisms in Asthma (G1000758). Y-HC, LR, and CC with CH were further supported through Pilot and Feasibility grants from the Alpha 1 Foundation. This research also received support from the National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. BG was supported by the MRC (UK), and the NIHR Leicester Biomedical Research Centre-Respiratory. Publisher Copyright: © Copyright © 2021 Chen, Cheadle, Rice, Pfeffer, Dimeloe, Gupta, Bush, Gooptu and Hawrylowicz. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/8/12

Y1 - 2021/8/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85113746810&partnerID=8YFLogxK

U2 - 10.3389/fnut.2021.667203

DO - 10.3389/fnut.2021.667203

M3 - Article

SN - 2296-861X

VL - 8

JO - Frontiers in Nutrition

JF - Frontiers in Nutrition

M1 - 667203

ER -