Vitamin D deficiency after allogeneic hematopoietic cell transplantation promotes T-cell activation and is inversely associated with an EZH2-ID3 signature.
Vitamin D deficiency after allogeneic hematopoietic cell transplantation promotes T-cell activation and is inversely associated with an EZH2-ID3 signature.
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DOI：
10.1016/j.jtct.2021.09.017
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发表时间：
2022-01
影响因子：
3.2
通讯作者：
Reshef R
中科院分区：
文献类型：
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作者：
Macedo R;Pasin C;Ganetsky A;Harle D;Wang XK;Belay K;Richman LP;Huffman AP;Vonderheide RH;Yates AJ;Porter DL;Wang Y;Zhang Y;Reshef R
在异基因造血细胞移植（HCT）受者中，维生素D促进从促炎到更耐受性免疫状态的转变。造成这种转变的主要机制尚未阐明。我们采用多方面的方法来评估53名HCT受者低维生素D水平的临床和免疫影响。我们使用28-plex流式细胞术检测免疫表型、血清细胞因子水平、t细胞细胞因子产生和t细胞全基因组转录。第30天的维生素D水平中位数为20 ng/mL，在接受清骨髓移植的年轻患者中缺乏维生素D很常见。维生素D水平低与CD8/Treg比值高有关；促炎细胞因子的血清水平和t细胞生成增加；以及通过PRC2/EZH2复合物进行无约束t细胞增殖和表观遗传调控的基因表达特征。免疫分型证实了高水平维生素D与激活的EZH2信号之间的密切联系，其特征是ID3的过表达，它在效应t细胞分化中起作用。我们的研究结果证明了维生素D在调节人类GVHD中t细胞功能中的关键作用，并确定了先前描述的与EZH2和ID3的相互作用，这种相互作用可能影响效应物分化，并对细胞治疗和其他形式的癌症免疫治疗有影响。
Vitamin D promotes a shift from a pro-inflammatory to a more tolerogenic immune state in allogeneic hematopoietic cell transplantation (HCT) recipients. The dominant mechanism responsible for this shift has not been elucidated. We took a multifaceted approach to evaluating the clinical and immunologic impact of low vitamin D levels in 53 HCT recipients. We used 28-plex flow cytometry for immunophenotyping, serum cytokine levels, T-cell cytokine production and T-cell whole genome transcription. The median day-30 vitamin D level was 20 ng/mL, and deficiency was common in younger patients undergoing myeloablative transplants. Low vitamin D levels were associated with a high CD8/Treg ratio; increased serum levels and T-cell production of proinflammatory cytokines; and a gene expression signature of unrestrained T-cell proliferation and epigenetic modulation through the PRC2/EZH2 complex. Immunophenotyping confirmed a strong association between high levels of vitamin D and an activated EZH2 signature, characterized by overexpression of ID3, which has a role in effector T-cell differentiation. Our findings demonstrate the critical role of vitamin D in modulating T-cell function in human GVHD and identify a previously undescribed interaction with EZH2 and ID3 which may impact effector differentiation and has implications to cell therapies and other forms of cancer immunotherapy.
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影响因子：
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