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首页> 外文期刊>The journal of clinical investigation >Differentiation and functional regulation of human fetal NK cells
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Differentiation and functional regulation of human fetal NK cells

机译:人胎儿NK细胞的分化和功能调控

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The human fetal immune system is naturally exposed to maternal allogeneic cells, maternal antibodies, and pathogens. As such, it is faced with a considerable challenge with respect to the balance between immune reactivity and tolerance. Here, we show that fetal natural killer (NK) cells differentiate early in utero and are highly responsive to cytokines and antibody-mediated stimulation but respond poorly to HLA class I–negative target cells. Strikingly, expression of killer-cell immunoglobulin-like receptors (KIRs) did not educate fetal NK cells but rendered them hyporesponsive to target cells lacking HLA class I. In addition, fetal NK cells were highly susceptible to TGF-β–mediated suppression, and blocking of TGF-β signaling enhanced fetal NK cell responses to target cells. Our data demonstrate that KIR-mediated hyporesponsiveness and TGF-β–mediated suppression are major factors determining human fetal NK cell hyporesponsiveness to HLA class I–negative target cells and provide a potential mechanism for fetal-maternal tolerance in utero. Finally, our results provide a basis for understanding the role of fetal NK cells in pregnancy complications in which NK cells could be involved, for example, during in utero infections and anti-RhD–induced fetal anemia.
机译:人类胎儿的免疫系统自然会暴露于母体同种异体细胞,母体抗体和病原体。因此,在免疫反应性和耐受性之间的平衡方面面临着相当大的挑战。在这里,我们显示出胎儿自然杀伤(NK)细胞在子宫内早期分化,对细胞因子和抗体介导的刺激高度反应,但对HLA I类阴性靶细胞反应较差。令人惊讶的是,杀伤细胞免疫球蛋白样受体(KIRs)的表达并不能教育胎儿NK细胞,但却使它们对缺乏I类HLA的靶细胞反应迟钝。此外,胎儿NK细胞高度易受TGF-β介导的抑制作用,并且TGF-β信号传导的阻断增强了胎儿NK细胞对靶细胞的反应。我们的数据表明,KIR介导的反应低下和TGF-β介导的抑制是决定人类胎儿NK细胞对HLA I类阴性靶细胞反应低下的主要因素,并为子宫内胎儿-母亲耐受性提供了潜在的机制。最后,我们的结果为了解胎儿NK细胞在妊娠并发症中的作用提供了基础,在这些并发症中,例如在子宫内感染和抗RhD引起的胎儿贫血期间,NK细胞可能参与其中。

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