Ashkar Ali A, Black Gordon P, Wei Qingxia, He Hong, Liang Luchuan, Head Judith R, Croy B Anne
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
J Immunol. 2003 Sep 15;171(6):2937-44. doi: 10.4049/jimmunol.171.6.2937.
In mouse and human, precursors of NK cell lineage home to decidualizing uteri. To assess the requirement for IL-15, an essential cytokine for NK differentiation in lymphoid tissue, on uterine NK (uNK) cell differentiation, implantation sites from IL-15(-/-) mice were analyzed histologically. IL-15(-/-) implantation sites had no uNK cells, no spiral-artery modification, and lacked the decidual integrity found in normal mice. IL-15(-/-) recipients of C57BL/6 marrow displayed similar pathology. However, implantation sites from recombination-activating gene-2(-/-)gamma(c)(-/-) (alymphoid) recipients of IL-15(-/-) marrow showed normal uNK cells, modified spiral arteries, and well-developed decidua basalis. Deletion of the IFN-regulatory factor (IRF)-1, but not IRF-2 (factors important in peripheral NK cell differentiation) limited but did not prevent uNK cell development. In situ hybridization localized IRF-1 largely to placental trophoblast cells. IRF-1(-/-) marrow transplanted into recombination-activating gene-2(-/-)gamma(c)(-/-) displayed competence for full uNK cell differentiation. IL-15 mRNA expression at implantation sites of IRF-1(-/-) and C57BL/6 was similar, suggesting that, unlike in bone marrow and spleen, IRF-1 does not regulate IL-15 in the pregnant uterus. Terminal differentiation of uNK cells was not promoted in pregnant IRF-1(-/-) mice by 5-day infusion of murine rIL-15, suggesting that IRF-1 deficiency rather than IL-15 deficiency limits uNK cell differentiation in these mice. Further, IRF-1 regulates placental growth, birth weight, and postnatal growth of offspring. These studies indicate that uNK cell development and maturation share some aspects with NK cell development in other tissues, but also display distinctive tissue-specific regulation.
在小鼠和人类中，自然杀伤（NK）细胞谱系的前体细胞会迁移至发生蜕膜化的子宫。为了评估白细胞介素-15（IL-15，淋巴组织中NK细胞分化所必需的细胞因子）对子宫NK（uNK）细胞分化的需求，对来自IL-15基因敲除（-/-）小鼠的着床部位进行了组织学分析。IL-15基因敲除小鼠的着床部位没有uNK细胞，没有螺旋动脉改变，并且缺乏正常小鼠中发现的蜕膜完整性。接受C57BL/6骨髓的IL-15基因敲除小鼠表现出类似的病理特征。然而，接受IL-15基因敲除小鼠骨髓的重组激活基因-2（-/-）γc（-/-）（无淋巴细胞）小鼠的着床部位显示出正常的uNK细胞、改变的螺旋动脉和发育良好的基底蜕膜。干扰素调节因子（IRF）-1的缺失（而非IRF-2的缺失，IRF-2是外周NK细胞分化中的重要因子）限制但并未阻止uNK细胞的发育。原位杂交显示IRF-1主要定位于胎盘滋养层细胞。移植到重组激活基因-2（-/-）γc（-/-）小鼠体内的IRF-1基因敲除骨髓具有完全uNK细胞分化的能力。IRF-1基因敲除小鼠和C57BL/6小鼠着床部位的IL-15 mRNA表达相似，这表明与骨髓和脾脏不同，IRF-1在妊娠子宫中不调节IL-15。在妊娠的IRF-1基因敲除小鼠中，连续5天输注鼠源重组IL-15并不能促进uNK细胞的终末分化，这表明在这些小鼠中，是IRF-1缺陷而非IL-15缺陷限制了uNK细胞的分化。此外，IRF-1调节胎盘生长、出生体重和后代的出生后生长。这些研究表明，uNK细胞的发育和成熟与其他组织中NK细胞的发育有一些共同之处，但也表现出独特的组织特异性调节。
