HLA-G expression levels influence the tolerogenic activity of human DC-10
HLA-G expression levels influence the tolerogenic activity of human DC-10
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DOI：
10.3324/haematol.2014.113803
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发表时间：
2015-04-01
期刊：
影响因子：
10.1
通讯作者：
Gregori, Silvia
中科院分区：
文献类型：
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作者：
Amodio, Giada;Comi, Michela;Gregori, Silvia
人类白细胞抗原（HLA）-G是一种非经典的HLA I类分子，具有已知的免疫调节功能。我们的研究小组鉴定了一个名为DC-10的人类树突状细胞亚群，它通过白细胞介素-10依赖性HLA-G/ILT 4途径诱导产生适应性白细胞介素-10的T调节1型（Tr 1）细胞。在这项研究中，我们的目的是确定DC-10介导的Tr 1细胞分化的HLA-G的作用。我们分析了来自67名健康供体的体外分化的DC-10的HLA-G位点的3'非翻译区的表型、功能和遗传变异。我们发现DC-10上的HLA-G表达是供体依赖性的。功能研究表明，DC-10，独立于HLA-G表达，分泌白细胞介素-10和可忽略的水平的白细胞介素-12。有趣的是，与具有低HLA-G的DC-10相比，具有高HLA-G的DC-10促进含有显著更高频率的Tr 1细胞的同种异体特异性无反应性T细胞，所述Tr 1细胞被定义为产生白细胞介素-10（P=0.0121）或CD 49 b +LAG-3+（P=0.0031）T细胞。我们发现DC-10上的HLA-G表达是遗传印记的，与该基因的3'非翻译区的特定变异相关，并且它可以通过microRNA介导的转录后调节进行微调。这些数据突出了HLA-G在增强DC-10致耐受性活性中的重要作用，并证实DC-10产生白细胞介素-10是必要的，但不足以以高频率促进Tr 1细胞。这些对HLA-G在DC-10介导的Tr 1细胞诱导中的作用的新见解为基于Tr 1或DC-10的细胞治疗方法的临床应用提供了额外的信息。
Human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule with known immune-modulatory functions. Our group identified a subset of human dendritic cells, named DC-10, that induce adaptive interleukin-10-producing T regulatory type 1 (Tr1) cells via the interleukin-10-dependent HLA-G/ILT4 pathway. In this study we aimed at defining the role of HLA-G in DC-10-mediated Tr1 cell differentiation. We analyzed phenotype, functions, and genetic variations in the 3' untranslated region of the HLA-G locus of in vitro-differentiated DC-10 from 67 healthy donors. We showed that HLA-G expression on DC-10 is donor-dependent. Functional studies demonstrated that DC-10, independently of HLA-G expression, secrete interleukin-10 and negligible levels of interleukin-12. Interestingly, DC-10 with high HLA-G promote allo-specific anergic T cells that contain a significantly higher frequency of Tr1 cells, defined as interleukin-10-producing (P=0.0121) or CD49b+LAG-3+ (P=0.0031) T cells, compared to DC-10 with low HLA-G. We found that the HLA-G expression on DC-10 is genetically imprinted, being associated with specific variations in the 3' untranslated region of the gene, and it may be finely tuned by microRNA-mediated post-transcriptional regulation. These data highlight the important role of HLA-G in boosting DC-10 tolerogenic activity and confirm that interleukin-10 production by DC-10 is necessary but not sufficient to promote Tr1 cells at high frequency. These new insights into the role of HLA-G in DC-10-mediated induction of Tr1 cells provide additional information for clinical use in Tr1- or DC-10-based cell therapy approaches.