Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3
Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3
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DOI：
10.1084/jem.186.9.1597
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发表时间：
1997-11-03
影响因子：
15.3
通讯作者：
Spits, H
中科院分区：
文献类型：
--
作者：
Heemskerk, MHM;Blom, B;Spits, H
双能T/自然杀伤（NK）祖细胞存在于人胸腺中。尽管它们具有双潜能能力，但这些祖细胞主要发育为胸腺中的T细胞。控制这种发育选择的机制尚不清楚。在这里，我们提出的证据表明，基本螺旋环螺旋（bHLH）转录因子家族的成员决定了NWT细胞祖细胞的谱系规范。通过逆转录病毒介导的基因转移，在CD 34（+）祖细胞中表达天然显性负性HLH因子Id 3，其阻断许多已知bHLH因子的转录活性。Id 3的组成型表达完全阻断了胎儿胸腺器官培养物（FTOC）中CD 34（+）细胞向T细胞的发育。相比之下，在FTOC中向NK细胞的发育得到增强。因此，bHLH转录因子的活性对于双能前体的T谱系分化是必需的，在缺乏bHLH转录因子的情况下，选择导致NK细胞发育的默认途径。我们的研究结果确定了人类早期淋巴前体细胞谱系特化的分子开关。
Bipotential T/natural killer (NK) progenitor cells are present in the human thymus. Despite their bipotential capacity, these progenitors develop predominantly to T cells in the thymus. The mechanisms controlling this developmental choice are unknown. Here we present evidence that a member(s) of the family of basic helix loop helix (bHLH) transcription factors determines lineage specification of NWT cell progenitors. The natural dominant negative HLH factor Id3, which blocks transcriptional activity of a number of known bHLH factors, was expressed in CD34(+) progenitor cells by retrovirus-mediated gene transfer. Constitutive expression of Id3 completely blocks development of CD34(+) cells into T cells in a fetal thymic organ culture (FTOC). In contrast, development into NK cells in an FTOC is enhanced. Thus, the activity of a bHLH transcription factor is necessary for T lineage differentiation of bipotential precursors, in the absence of which a default pathway leading to NK cell development is chosen. Our results identify a molecular-switch for lineage specification in early lymphoid precursors of humans.