Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
J Clin Invest. 2013 Sep;123(9):3889-901. doi: 10.1172/JCI68989. Epub 2013 Aug 15.
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.
人类胎儿的免疫系统会自然接触到母体的同种异体细胞、母体抗体和病原体。因此，它面临着免疫反应和耐受之间平衡的巨大挑战。在这里，我们表明胎儿自然杀伤 (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敏感，但对 HLA Ⅰ类阴性靶细胞反应不佳。引人注目的是，杀伤细胞免疫球蛋白样受体 (KIR) 的表达并没有使胎儿 NK 细胞成熟，而是使它们对缺乏 HLA Ⅰ类的靶细胞反应迟钝。此外，胎儿 NK 细胞对 TGF-β 介导的抑制作用高度敏感，阻断 TGF-β 信号通路可增强胎儿 NK 细胞对靶细胞的反应。我们的数据表明，KIR 介导的低反应性和 TGF-β 介导的抑制是决定人类胎儿 NK 细胞对 HLA Ⅰ类阴性靶细胞低反应性的主要因素，并为子宫内胎儿-母体耐受提供了潜在的机制。最后，我们的结果为理解胎儿 NK 细胞在可能涉及 NK 细胞的妊娠并发症中的作用提供了基础，例如在宫内感染和抗 RhD 诱导的胎儿贫血期间。
