GATA2 regulates dendritic cell differentiation.
GATA2 regulates dendritic cell differentiation.
复制标题
DOI：
10.1182/blood-2016-02-698118
复制
发表时间：
2015-12
期刊：
影响因子：
20.3
通讯作者：
Koichi Onodera;T. Fujiwara;Y. Onishi;Ari Itoh-Nakadai;Y. Okitsu;N. Fukuhara;K. Ishizawa;R. Shimizu;Masayuki Yamamoto;H. Harigae
中科院分区：
文献类型：
--
作者：
Koichi Onodera;T. Fujiwara;Y. Onishi;Ari Itoh-Nakadai;Y. Okitsu;N. Fukuhara;K. Ishizawa;R. Shimizu;Masayuki Yamamoto;H. Harigae
树突状细胞 (DC) 是重要的免疫反应调节剂；然而，DC分化的机制尚不完全清楚。杂合种系 GATA2 突变可诱发 GATA2 缺陷综合征，其特征是单核细胞减少症、骨髓增生异常/急性髓系白血病的易感性以及 DC 群体的大幅减少，这与病毒感染的易感性增加、吞噬作用受损和细胞因子产生减少有关。为了明确 GATA2 在 DC 分化和功能中的作用，我们研究了 Gata2 条件敲除和单倍体不足的小鼠。 Gata2 条件性缺陷显着降低了 DC 计数，而 Gata2 单倍体不足并不影响该群体。从Lin(-)Sca-1(+)Kit(+)细胞、常见的髓系限制性祖细胞和常见的树突状细胞前体体外生成DC需要GATA2，但常见的淋巴限制性祖细胞或粒细胞-巨噬细胞祖细胞不需要GATA2，这表明GATA2在DC分化的髓系途径中发挥作用。此外，表达谱表明，在 Gata2 缺陷的 DC 祖细胞中，骨髓相关基因（包括 mafb）的表达减少，而 T 淋巴细胞相关基因（包括 Gata3 和 Tcf7）的表达增加。此外，发现GATA2与Gata3下游区域190-kb的增强子元件结合，报告分析显示，将该增强子区域添加到Gata3启动子后，荧光素酶活性显着降低，通过删除Gata3+190内的GATA序列可以恢复荧光素酶活性。这些结果表明，GATA2 通过调节 DC 祖细胞中的谱系特异性转录因子，从而促进 DC 分化，在骨髓细胞与 T 淋巴细胞谱系的细胞命运规范中发挥重要作用。
Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germ line GATA2 mutations induce GATA2-deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia/acute myeloid leukemia, and a profoundly reduced DC population, which is associated with increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. To define the role of GATA2 in DC differentiation and function, we studied Gata2 conditional knockout and haploinsufficient mice. Gata2 conditional deficiency significantly reduced the DC count, whereas Gata2 haploinsufficiency did not affect this population. GATA2 was required for the in vitro generation of DCs from Lin(-)Sca-1(+)Kit(+) cells, common myeloid-restricted progenitors, and common dendritic cell precursors, but not common lymphoid-restricted progenitors or granulocyte-macrophage progenitors, suggesting that GATA2 functions in the myeloid pathway of DC differentiation. Moreover, expression profiling demonstrated reduced expression of myeloid-related genes, including mafb, and increased expression of T-lymphocyte-related genes, including Gata3 and Tcf7, in Gata2-deficient DC progenitors. In addition, GATA2 was found to bind an enhancer element 190-kb downstream region of Gata3, and a reporter assay exhibited significantly reduced luciferase activity after adding this enhancer region to the Gata3 promoter, which was recovered by GATA sequence deletion within Gata3 +190. These results suggest that GATA2 plays an important role in cell-fate specification toward the myeloid vs T-lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation.