A Recurrent Network Involving the Transcription Factors PU.1 and Gfi1 Orchestrates Innate and Adaptive Immune Cell Fates
A Recurrent Network Involving the Transcription Factors PU.1 and Gfi1 Orchestrates Innate and Adaptive Immune Cell Fates
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DOI：
10.1016/j.immuni.2009.07.011
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发表时间：
2009-10-16
期刊：
影响因子：
32.4
通讯作者：
Singh, Harinder
中科院分区：
文献类型：
--
作者：
Spooner, Chauncey J.;Cheng, Jason X.;Singh, Harinder
转录因子PU.1由Sfpi1基因编码，以分级的方式调节巨噬细胞与B细胞的生成；其较高的浓度有利于巨噬细胞的命运。我们证明，Gfi1以髓系后代为代价，相互促进B细胞的命运选择。GFI1(-/-)多潜能前体细胞(MPPs)不能抑制PU.1的表达，因为Gfi1通过取代PU.1而抑制Sfpi1基因的表达。减弱由PU.1和Egr组成的转录模块可抑制Gfi1(-/-)MPPs的B系发育缺陷。最后，B细胞发育所需的转录因子lkaros促进了Gfi1的表达，并拮抗了PU.1的表达。我们的结果表明，在先天免疫系统中，用于指导细胞命运选择的核心转录调控网络已经被伊卡洛斯选中来协调B淋巴细胞的产生。这些发现对适应性免疫系统的进化具有重要意义。
The transcription factor PU.1, encoded by the Sfpi1 gene, functions in a graded manner to regulate macrophage versus B cell generation; its higher concentration favors the macrophage fate. We demonstrated that Gfi1 reciprocally promoted B cell fate choice at the expense of myeloid progeny. Gfi1(-/-) multipotential progenitors (MPPs) were unable to constrain the expression of PU.1 because Gfi1 functioned to repress the Sfpi1 gene by displacing PU.1 from positive autoregulatory elements. Attenuating a transcriptional module composed of PU.1 and Egr suppressed the B lineage developmental defects of Gfi1(-/-) MPPs. Finally lkaros, a transcription factor required for B cell development, promoted Gfi1 and antagonized PU.1 expression in MPPs. Our results reveal that a core transcriptional regulatory network used for directing cell fate choice in the innate immune system has been co-opted by lkaros to orchestrate B lymphocyte generation. These findings have important implications for the evolution of the adaptive immune system.