Department of Animal Science, Center for Reproductive Biology and Health, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, USA.
VA Medical Center, San Francisco, California, USA.
Biol Reprod. 2017 Jul 1;97(1):104-118. doi: 10.1093/biolre/iox061.
Natural killer (NK) cells are essential for establishment of human and rodent pregnancies. The function of these and other cytotoxic T cells (CTL) is controlled by stimulatory and inhibitory signaling. A role for cytotoxic cells during early pregnancy in cattle has not been described, but regulation of their function at the fetal-maternal interface is thought to be critical for conceptus survival. The hypothesis that the relative abundance of CTL and expression of inhibitory signaling molecules is increased by the conceptus during early pregnancy was tested. The proportions of lymphoid lineage cells and expression of inhibitory signaling molecules in the endometrium during early pregnancy in dairy heifers were determined using flow cytometry, immunofluorescence, and real-time PCR on days 17 and 20 of pregnancy and day 17 of the estrous cycle. Results revealed an increased percentage of NKp46+ and CD8+ cells in the uterus of pregnant heifers. Furthermore, a large percentage of uterine immune cells coexpressed these proteins. Compared to cyclic heifers, CD45+ uterine cells from pregnant heifers exhibited greater degranulation. Endometrium from pregnant heifers had greater mRNA abundance for the inhibitory molecules, CD274 and lymphocyte activating gene 3 (LAG3), and greater cytotoxic T lymphocyte-associated protein 4 (CTLA4), molecules that can interact with receptors on antigen-presenting cells and induce lymphocyte tolerance. This study demonstrates a dynamic regulation of both cytotoxic immune cells and tolerogenic molecules during the peri-implantation period that may be required to support establishment of pregnancy and placentation.
自然杀伤 (NK) 细胞对于人类和啮齿动物的妊娠建立至关重要。这些细胞和其他细胞毒性 T 细胞 (CTL) 的功能受到刺激和抑制信号的控制。虽然在牛的早期妊娠中尚未描述细胞毒性细胞的作用，但认为它们在母体-胎儿界面的功能调节对于胚胎存活至关重要。本研究旨在检验胚胎在早期妊娠期间通过调节 CTL 及其抑制性信号分子的相对丰度的假说。通过流式细胞术、免疫荧光和实时 PCR，在妊娠第 17 天和第 20 天以及发情周期第 17 天，检测了奶牛小母牛早期妊娠期间子宫内膜中淋巴谱系细胞的比例和抑制性信号分子的表达。结果显示，妊娠小母牛子宫中 NKp46+和 CD8+细胞的比例增加。此外，大量的子宫免疫细胞共表达这些蛋白。与发情周期小母牛相比，妊娠小母牛的 CD45+子宫细胞脱颗粒更多。与发情周期小母牛相比，妊娠小母牛的子宫内膜中抑制分子 CD274 和淋巴细胞激活基因 3 (LAG3) 的 mRNA 丰度更高，且细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA4) 更高，这些分子可以与抗原呈递细胞上的受体相互作用并诱导淋巴细胞耐受。本研究表明，在植入前期间，细胞毒性免疫细胞和耐受相关分子的动态调节可能对于支持妊娠建立和胎盘形成是必需的。
