Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBPα and PU.1 transcription factors
Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBPα and PU.1 transcription factors
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DOI：
10.1016/j.immuni.2006.09.011
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发表时间：
2006-11-01
期刊：
影响因子：
32.4
通讯作者：
Graf, Thomas
中科院分区：
文献类型：
--
作者：
Laiosa, Catherine V.;Stadtfeld, Matthias;Graf, Thomas
多能前体进入胸腺后，T系细胞的分化潜力受到限制，并伴有转录因子C/EBP α和PU.1的下调。为了研究这一限制性点，我们表达了C/EBP α和PU.1。发现C/EBP α（和C/EBP β）诱导了功能性巨噬细胞的形成。相比之下，PU.1在相同的培养条件下将它们转化为骨髓树突状细胞。C/EBP α诱导的重编程是复杂的，因为一些但不是全部的髓细胞标志物的上调需要内源性pu 1。Notch信号部分抑制C/EBP α诱导的巨噬细胞形成，完全阻断pu .1诱导的树突状细胞形成。同样，细胞内Notch或转录因子GATA-3的表达抑制了C/EBP α诱导的谱系转换。我们的数据表明，承袭的T细胞祖细胞仍然容易受到髓系转录因子的谱系指导作用，并表明Notch信号通过下调多谱系前体中的C/EBP α和PU.1来诱导T谱系限制。
The differentiation potential of T lineage cells becomes restricted soon after entry of multipotent precursors into the thymus and is accompanied by a downregulation of the transcription factors C/EBP alpha and PU.1. To investigate this restriction point, we have expressed C/EBP alpha and PU.1. in fully committed pre-T cells and found that C/EBP alpha (and C/EBP beta) induced the formation of functional macrophages. In contrast, PU.1 converted them into myeloid dendritic cells under identical culture conditions. C/EBP alpha-induced reprogramming is complex because upregulation of some but not all myelomonocytic markers required endogenous PU.1. Notch signaling partially inhibited C/EBP alpha-induced macrophage formation and completely blocked PU.1-induced dendritic cell formation. Likewise, expression of intracellular Notch or the transcription factor GATA-3 inhibited C/EBP alpha-induced lineage conversion. Our data show that committed T cell progenitors remain susceptible to the lineage instructive effects of myeloid transcription factors and suggest that Notch signaling induces T lineage restriction by downregulating C/EBP alpha and PU.1 in multilineage precursors.