Batf3 maintains autoactivation of Irf8 for commitment of a CD8α(+) conventional DC clonogenic progenitor.
Batf3 maintains autoactivation of Irf8 for commitment of a CD8α(+) conventional DC clonogenic progenitor.
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DOI：
10.1038/ni.3197
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发表时间：
2015-07
影响因子：
30.5
通讯作者：
Murphy KM
中科院分区：
文献类型：
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作者：
Grajales-Reyes GE;Iwata A;Albring J;Wu X;Tussiwand R;Kc W;Kretzer NM;Briseño CG;Durai V;Bagadia P;Haldar M;Schönheit J;Rosenbauer F;Murphy TL;Murphy KM
转录因子Batf3和IRF8是CD8 α +常规树突状细胞（cDC）发育所必需的，但其作用的基础尚不清楚。在这里，我们鉴定了两种新的Zbtb46+祖细胞，它们分别产生CD8 α +和CD4 + cDC，并直接产生于共同DC祖细胞（CDP）。CDP中的Irf8表达取决于先前的PU.1依赖性自激活，并且前CD8 DC祖细胞的特化需要IRF8而不是Batf3。然而，在CD8前DC特化后，Irf8自激活在Irf8超增强子内含有多个AP1-IRF复合元件（AICE）的CD8 α + cDC特异性增强子处变为Batf3依赖性。来自Batf3 −/−小鼠的特异性朝向前CD8 DC的CDP由于Irf8自激活的衰减而不能完成CD8 α + cDC发育，并转向CD4 + cDC谱系。
The transcription factors Batf3 and IRF8 are required for development of CD8α+ conventional dendritic cells (cDCs), but the basis for their actions was unclear. Here, we identify two novel Zbtb46+ progenitors that separately generate CD8α+ and CD4+ cDCs and arise directly from the common DC progenitor (CDP). Irf8 expression in the CDP depends on prior PU.1-dependent autoactivation, and specification of pre-CD8 DC progenitors requires IRF8 but not Batf3. However, upon pre-CD8 DC specification, Irf8 autoactivation becomes Batf3-dependent at a CD8α+ cDC-specific enhancer containing multiple AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3−/− mice that specify toward pre-CD8 DCs fail to complete CD8α+ cDC development due to decay of Irf8 autoactivation, and divert to the CD4+ cDC lineage.