Chen Yin-Huai, Cheadle Charlotte E, Rice Louise V, Pfeffer Paul E, Dimeloe Sarah, Gupta Atul, Bush Andrew, Gooptu Bibek, Hawrylowicz Catherine M
Peter Gorer Department of Immunobiology (Formerly Asthma, Allergy and Lung Biology), School of Immunology and Microbial Sciences, King's College London, London, United Kingdom.
Medical Research Council and Asthma UK Centre for Allergic Mechanisms of Asthma, Guy's Hospital, King's College London, London, United Kingdom.
Front Nutr. 2021 Aug 12;8:667203. doi: 10.3389/fnut.2021.667203. eCollection 2021.
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)D3) treatment induced alpha-1 antitrypsin (AAT) expression in CD4+, but not CD8+ T cells, with evidence supporting an immunoregulatory role. 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)D3-induced upregulation of AAT by vitamin D in CD8+ T cells and correlated circulating vitamin D levels with lung AAT levels . 1,25(OH)D3 in combination with TGF-β1 increased AAT expression by CD8+ T cells, as well as and 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)D3 was associated with increased TGF-β bioactivity and neutralisation of TGF-β partially abrogated 1,25(OH)D3-induced gene expression. Neither CD4+ nor CD8+ T cells responded to the circulating vitamin D precursor, 25-hydroxyvitamin D3 for induction of , suggesting that local generation of 1,25(OH)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)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)D3-induced AAT. However, CD8+ T cells from adults with AAT-deficiency, homozygous for the Z allele of , were unable to mount this response. AAT levels in the airways of children with asthma and controls correlated with circulating 25(OH)D3. 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 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.
维生素D可上调促进呼吸道健康的抗炎和抗菌途径。皮肤暴露于阳光下会启动维生素D的合成，然而，可能需要营养补充来解决维生素D缺乏问题，例如在冬季或由于文化限制等情况。我们最近报道，1α,25 - 二羟基维生素D3（1,25(OH)D3）处理可诱导CD4 + 而非CD8 + T细胞中α - 1抗胰蛋白酶（AAT）的表达，有证据支持其免疫调节作用。为了进一步了解维生素D、肺AAT水平和T淋巴细胞之间的关系，我们研究了TGF - β是否作为1,25(OH)D3诱导CD8 + T细胞中AAT上调的辅助因子，以及循环维生素D水平与肺AAT水平之间的相关性。1,25(OH)D3与TGF - β1联合可增加CD8 + T细胞中AAT的表达以及α基因的表达，这可能部分解释了对TGF - β的需求。CD4 + T细胞可能也需要以TGF - β作为辅助因子进行自分泌刺激，因为1,25(OH)D3与TGF - β生物活性增加相关，而TGF - β的中和部分消除了1,25(OH)D3诱导的基因表达。CD4 + 和CD8 + T细胞对循环维生素D前体25 - 羟基维生素D3诱导的均无反应，这表明需要局部生成1,25(OH)D3。转录基因谱研究先前表明，人支气管上皮细胞对1,25(OH)D3反应迅速增加TGF - β2基因表达。在此，人上皮细胞对前体25(OH)D3反应以增加生物活性TGF - β的合成。CD8 + T细胞对TGF - β1和TGF - β2的反应相当，以增加1,25(OH)D3诱导的AAT。然而，来自AAT缺乏且为纯合Z等位基因的成年人的CD8 + T细胞无法产生这种反应。哮喘儿童和对照组气道中的AAT水平与循环25(OH)D3相关。在临床人群中，维生素D可增加人T细胞中AAT的表达，而对于纯合Z等位基因个体的T细胞，这种反应受损。此外，还报道了循环维生素D与气道AAT之间的相关性。我们提出，维生素D诱导的AAT有助于局部免疫调节以及先前归因于维生素D的气道健康效应。
