Expression of BMPRIA on human thymic NK cell precursors: role of BMP signaling in intrathymic NK cell development
Expression of BMPRIA on human thymic NK cell precursors: role of BMP signaling in intrathymic NK cell development
复制标题
DOI：
10.1182/blood-2011-07-370650
复制
发表时间：
2012-02-23
期刊：
影响因子：
20.3
通讯作者：
Vicente, Angeles
中科院分区：
文献类型：
--
作者：
Hidalgo, Laura;Martinez, Victor G.;Vicente, Angeles
骨形态发生蛋白(BMP)信号通路调节包括胸腺在内的多种组织中多种细胞的存活、增殖和分化。以前的报告表明，BMP信号负向调节T细胞的发育。在这里，我们研究了表达IA型BMP受体(BMPRIA)的早期人类胸腺内祖细胞亚群，并提供了CD34(+)CD1a(-)BMPRIA(+)前体细胞主要表达与NK细胞谱系相关的表面细胞标记和转录因子的证据。这些CD34(+)细胞在人-鼠胎胸腺器官嵌合培养中与胸腺基质细胞共培养时，以及在SCF和IL-15的存在下，大多分化为具有功能的CD56(+)自然杀伤(NK)细胞。此外，自分泌BMP信号可以通过调节NK细胞谱系所需的关键转录因子(如ID3和Nfil3)以及IL-15受体的组成部分CD122的表达来促进胸腺NK细胞的分化。随后，IL-15可以扩大IL-15应答的NK细胞前体细胞群，其作用是通过胸腺NK细胞分化的最后步骤中的BMP信号介导的。我们的结果强烈表明，BMPRIA表达识别人胸腺NK细胞前体，BMP信号与人胸腺NK细胞分化有关。(血。2012年；119(8)：1861-1871)
The bone morphogenetic protein (BMP) signaling pathway regulates survival, proliferation, and differentiation of several cell types in multiple tissues, including the thymus. Previous reports have shown that BMP signaling negatively regulates T-cell development. Here, we study the subpopulation of early human intrathymic progenitors expressing the type IA BMP receptor (BMPRIA) and provide evidence that CD34(+)CD1a(-)BMPRIA(+) precursor cells mostly express surface cell markers and transcription factors typically associated with NK cell lineage. These CD34(+) cells mostly differentiate into functional CD56(+) natural killer (NK) cells when they are cocultured with thymic stromal cells in chimeric human-mouse fetal thymic organ cultures and also in the presence of SCF and IL-15. Moreover, autocrine BMP signaling can promote the differentiation of thymic NK cells by regulating the expression of key transcription factors required for NK cell lineage (eg, Id3 and Nfil3) as well as one of the components of IL-15 receptor, CD122. Subsequently, the resulting population of IL-15-responsive NK cell precursors can be expanded by IL-15, whose action is mediated by BMP signaling during the last steps of thymic NK cell differentiation. Our results strongly suggest that BMPRIA expression identifies human thymic NK cell precursors and that BMP signaling is relevant for NK cell differentiation in the human thymus. (Blood. 2012;119(8):1861-1871)