Laiosa Catherine V, Stadtfeld Matthias, Xie Huafeng, de Andres-Aguayo Luisa, Graf Thomas
Department of Developmental and Molecular Biology and the Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Immunity. 2006 Nov;25(5):731-44. doi: 10.1016/j.immuni.2006.09.011.
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.
多能前体细胞进入胸腺后不久，T谱系细胞的分化潜能就受到限制，同时转录因子C/EBPα和PU.1的表达下调。为了研究这个限制点，我们在完全定向的前T细胞中表达了C/EBPα和PU.1，发现C/EBPα（和C/EBPβ）诱导了功能性巨噬细胞的形成。相比之下，在相同的培养条件下，PU.1将它们转化为髓样树突状细胞。C/EBPα诱导的重编程很复杂，因为一些但不是所有髓单核细胞标志物的上调需要内源性PU.1。Notch信号通路部分抑制C/EBPα诱导的巨噬细胞形成，并完全阻断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C/EBPα诱导的谱系转换。我们的数据表明，定向的T细胞祖细胞仍然易受髓样转录因子的谱系指导作用影响，并表明Notch信号通路通过下调多谱系前体细胞中的C/EBPα和PU.1来诱导T谱系限制。
