Deficiency of transcription factor RelB perturbs myeloid and DC development by hematopoietic-extrinsic mechanisms
Deficiency of transcription factor RelB perturbs myeloid and DC development by hematopoietic-extrinsic mechanisms
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DOI：
10.1073/pnas.1619863114
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发表时间：
2017-04-11
影响因子：
11.1
通讯作者：
Murphy, Kenneth M.
中科院分区：
文献类型：
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作者：
Briseno, Carlos G.;Gargaro, Marco;Murphy, Kenneth M.
RelB是一种NF-κ B B家族转录因子，在NF-κ B诱导激酶（NIK）和TNF受体家族成员（包括α光氧蛋白-β受体（LT β R）和CD 40）下游的非经典途径中活化。早期分析表明，RelB是经典树突状细胞（cDC）发育所必需的，这是基于RelB（-/-）小鼠中cDC的严重减少，其与B和T细胞中的深度骨髓扩增和扰动相关。随后对从野生型和Relb（-/-）骨髓产生的辐射嵌合体的分析表明，RelB对某些谱系发挥细胞外源性作用，但仍不清楚RelB对cDC发育的影响是细胞内源性的还是外源性的。在这里，我们使用一系列放射嵌合体重新评估了RelB在cDC和骨髓发育中的作用。我们发现，除了Notch 2和LT β R依赖的脾脏CD 4（+）cDC 2亚群外，大多数cDC亚群的发育对RelB没有细胞内在的要求。这些结果表明RelB在DC开发中的作用相对有限。此外，Relb（-/-）小鼠中的骨髓扩增是由RelB的造血外在作用引起的。这一结果表明，有一个未被认识到的，但关键的作用，RelB在非造血生态位，控制正常的骨髓。
RelB is an NF-kappa B family transcription factor activated in the noncanonical pathway downstream of NF-kappa B-inducing kinase (NIK) and TNF receptor family members including lymphotoxin-beta receptor (LT beta R) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in Relb(-/-) mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and Relb(-/-) bone marrow showed that RelB exerts cell-extrinsic actions on some lineages, but it has remained unclear whether the impact of RelB on cDC development is cell-intrinsic or -extrinsic. Here, we reevaluated the role of RelB in cDC and myeloid development using a series of radiation chimeras. We found that there was no cell-intrinsic requirement for RelB for development of most cDC subsets, except for the Notch2- and LT beta R-dependent subset of splenic CD4(+) cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in Relb(-/-) mice resulted from hematopoietic-extrinsic actions of RelB. This result suggests that there is an unrecognized but critical role for RelB within the nonhematopoietic niche that controls normal myelopoiesis.