Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis.
Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis.
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DOI：
10.3389/fimmu.2020.598727
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发表时间：
2020
影响因子：
7.3
通讯作者：
Astier AL
中科院分区：
文献类型：
--
作者：
Killick J;Hay J;Morandi E;Vermeren S;Kari S;Angles T;Williams A;Damoiseaux J;Astier AL
多发性硬化（MS）是中枢神经系统（CNS）的慢性炎症性疾病，其中T细胞迁移到CNS中是发病机制的关键。MS患者表现出受损的调节性T细胞群，Foxp 3 + T细胞和I型调节性T细胞（Tr 1）功能失调。MS是一种多因素疾病，维生素D缺乏与疾病有关。在此，我们研究了1，25（OH）2D 3对CD 4 + T细胞的影响，CD 4 + T细胞被CD 28共激活以诱导多克隆活化，或被补体调节剂CD 46共激活以促进Tr 1分化。添加1，25（OH）2D 3导致从健康供体或MS患者分离的CD 28和CD 46共刺激T细胞上粘附分子的差异表达。1，25（OH）2D 3有利于Tr 1运动，尽管维生素D-CD 46串扰突出表现为VDR表达增加以及CD 46共刺激T细胞中CYP 24 A1和miR-9增加。此外，对补充维生素D的MS患者队列的T细胞上的CD 46表达的分析显示，与循环维生素D水平呈负相关。此外，t-分布随机邻居嵌入（t-SNE）分析允许可视化和识别的集群增加维生素D补充剂，但不是安慰剂，表现出类似的粘附表型，在体外观察到的。总的来说，我们的数据显示维生素D和CD 46之间的串扰允许维生素D对Tr 1细胞的优先作用，为MS中重要的可改变环境因素的作用提供了新的关键见解。
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease. Herein, we examined the impact of 1,25(OH)2D3 on CD4+ T cells coactivated by either CD28 to induce polyclonal activation or by the complement regulator CD46 to promote Tr1 differentiation. Addition of 1,25(OH)2D3 led to a differential expression of adhesion molecules on CD28- and CD46-costimulated T cells isolated from both healthy donors or from patients with MS. 1,25(OH)2D3 favored Tr1 motility though a Vitamin D-CD46 crosstalk highlighted by increased VDR expression as well as increased CYP24A1 and miR-9 in CD46-costimulated T cells. Furthermore, analysis of CD46 expression on T cells from a cohort of patients with MS supplemented by vitamin D showed a negative correlation with the levels of circulating vitamin D. Moreover, t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis allowed the visualization and identification of clusters increased by vitamin D supplementation, but not by placebo, that exhibited similar adhesion phenotype to what was observed in vitro. Overall, our data show a crosstalk between vitamin D and CD46 that allows a preferential effect of Vitamin D on Tr1 cells, providing novel key insights into the role of an important modifiable environmental factor in MS.