ORIGINS AND FUNCTIONS OF UTERINE NATURAL KILLER CELLS IN PREGNANCY

妊娠期子宫自然杀伤细胞的起源和功能

• 批准号: 10451584
• 负责人: Wayne M. Yokoyama
• 金额: $ 56.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-13 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451584
• 关键词: Activities of Daily Living; Affect; Biological; Blood Vessels; CRISPR/Cas technology; Cellular biology; Clinical; Decidual Cell Reactions; Dependence; Epidemiology; Evolution; Family; Fetal Tissues; Fetus; Gene Targeting; Genes; Genotype; Goals; Home; Human; Individual; Knockout Mice; Laboratories; Lead; Leukocytes; Ligands; Maternal-Fetal Exchange; Mus; Natural Killer Cells; Organ; Outcome; Placentation; Play; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Uterus; Process; Property; Receptor Cell; Reproduction; Role; Time; Tissues; Uterus; epidemiology study; experimental study; fetal; genome editing; in vivo; insight; killer immunoglobulin-like receptor; pregnancy disorder; pregnant; receptor; transcription factor

Epidemiological studies have associated preeclampsia outcomes with genotypes of receptors on maternal natural killer (NK) cells, and genotypes of their cognate HLA class I (HLA-I) ligands in fetuses. These clinical findings have been replicated and strongly suggest that uterine NK (uNK) cells, the most abundant leukocytes at the maternal-fetal interface, specifically use their receptors to recognize HLA-I on fetal tissues, thereby playing vital roles in normal placentation, probably by affecting the vasculature which is abnormal in preeclampsia. Although it is challenging to study these possibilities in human reproduction, and we acknowledge that there are species-specific differences between human and mouse pregnancy, studies of mouse NK cells can yield important conceptual insight, as demonstrated numerous times previously in NK cell biology. Recent studies from the applicant's laboratory indicate that mouse organs, including the virgin uterus, contain both circulating “conventional” NK (cNK) cells and tissue-resident NK (trNK) cells that reside in the organ and do not recirculate. cNK and trNK cells from different organs represent distinct lineages of NK cells because they have differences in transcription factor dependencies. Moreover, cNK and trNK cells have different functional capacities. Finally, the Ly49 family of receptors are the functional equivalents to the human NK cell receptors implicated in preeclampsia. These considerations lead to the following proposed Specific Aims: 1) Determine contributions of cNK and trNK cells to uNK cells in pregnancy and decidualization; 2) Examine transcription factor dependence of uNK cells; and 3) Determine role of Ly49 receptors in pregnancy. Thus, these studies will provide major insight into the role of uNK cells in pregnancy, the major long-term objective of this proposal.

流行病学研究将先兆子痫的结果与母亲受体的基因型相关联 自然杀伤 (NK) 细胞及其胎儿中同源 HLA I 类 (HLA-I) 配体的基因型。 研究结果已得到重复，强烈表明子宫 NK (uNK) 细胞是最丰富的白细胞 在母胎界面，专门利用其受体识别胎儿组织上的 HLA-I，从而 在正常胎盘形成中发挥重要作用，可能是通过影响异常的脉管系统 尽管研究人类生殖中的这些可能性具有挑战性，但我们 承认人类和小鼠怀孕之间存在物种特异性差异，研究 小鼠 NK 细胞可以产生重要的概念见解，正如之前在 NK 中多次证明的那样 申请人实验室的最新研究表明，小鼠器官，包括处女器官 子宫内含有循环的“传统”NK (cNK) 细胞和组织驻留 NK (trNK) 细胞 来自不同器官的 cNK 和 trNK 细胞代表不同的 NK 谱系。 细胞，因为它们在转录因子依赖性方面存在差异此外，cNK 和 trNK 细胞也有差异。 最后，Ly49 受体家族的功能与人类相同。 这些考虑导致了以下提出的具体建议。 目的： 1) 确定 cNK 和 trNK 细胞在妊娠和蜕膜化过程中对 uNK 细胞的贡献； 检查 uNK 细胞的转录因子依赖性；3) 确定 Ly49 受体在妊娠中的作用。 因此，这些研究将为了解 uNK 细胞在妊娠中的作用提供重要见解，而妊娠是主要的长期研究 本提案的目标。

项目成果

Cutting Edge: Local Proliferation of Uterine Tissue-Resident NK Cells during Decidualization in Mice.

• DOI: 10.4049/jimmunol.1800651
• 发表时间: 2018-11-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Sojka DK;Yang L;Plougastel-Douglas B;Higuchi DA;Croy BA;Yokoyama WM
• 通讯作者: Yokoyama WM

Uterine natural killer cells: To protect and to nurture.

子宫自然杀伤细胞：保护和培育。

• DOI: 10.1002/bdr2.1419
• 发表时间: 2018-12-01
• 期刊: Birth defects research
• 影响因子: 2.1
• 作者: Sojka DK;Yang L;Yokoyama WM
• 通讯作者: Yokoyama WM