Department of Animal Science, Center for Reproductive Biology and Health, Huck Institutes of the Life Science, Pennsylvania State University, University Park 16802.
J Dairy Sci. 2019 Apr;102(4):3766-3777. doi: 10.3168/jds.2018-15668. Epub 2019 Feb 1.
Infertility and subfertility reduce the economic viability of dairy production. Inflammation reduces conception rates in dairy cattle, but surprisingly little information exists about the populations and the functions of immune cells at the conceptus-maternal interface during the periattachment period in dairy cattle. Early pregnancy is accompanied by immune stimulation at insemination and conceptus secretion of IFN-τ, pregnancy-associated glycoproteins, prostaglandins, and other molecules whose effects on immune function during early pregnancy have not been determined. Our working hypothesis is that pregnancy induces changes in immune cell populations and functions that are biased toward immunological tolerance, tissue remodeling, and angiogenesis. This review summarizes current knowledge, starting with insemination and proceeding through early pregnancy, as this is the period of maximal embryo loss. Results indicated that early pregnancy is accompanied by a marked increase in the proportion of endometrial immune cells expressing markers for natural killer (CD335) cells and cytotoxic T cells (CD8) along with an increase in cells expressing major histocompatibility class II antigens (macrophages and dendritic cells). This is accompanied by increased abundance of mRNA for IL-15, a natural killer growth factor, and IL-10 in the endometrium during early pregnancy. Furthermore, expression of indoleamine 2,3 dioxygenase was 15-fold greater in pregnant compared with cyclic heifers at d 17, but then declined by d 20. This enzyme converts tryptophan to kynurenine, which alters immune function by creating a localized tryptophan deficiency and by activation of the aryl hydrocarbon receptor and induction of downstream tolerogenic mediators. Expression of the aryl hydrocarbon receptor is abundant in the bovine uterus, but its temporal and spatial regulation during early pregnancy have not been characterized. Pregnancy is also associated with increased expression of proteins known to inhibit immune activation, including programed cell death ligand-1 (CD274), lymphocyte activation gene-3 (CD223), and cytotoxic T-lymphocyte associated protein-4 (CD152). These molecules interact with receptors on antigen-presenting cells and induce lymphocyte tolerance. Current results support the hypothesis that early pregnancy signaling in dairy heifers involves changes in the proportions of immune cells in the endometrium as well as induction of molecules known to mediate tolerance. These changes are likely essential for uterine wall remodeling, placentation, and successful pregnancy.
不孕和不育会降低奶牛养殖的经济可行性。奶牛的炎症会降低受孕率，但令人惊讶的是，关于奶牛附着前阶段胚胎-母体界面免疫细胞的群体和功能的信息却很少。早期妊娠伴随着受精时的免疫刺激和 IFN-τ、妊娠相关糖蛋白、前列腺素和其他分子的分泌，这些分子在早期妊娠期间对免疫功能的影响尚未确定。我们的工作假设是，妊娠诱导免疫细胞群体和功能的变化，偏向于免疫耐受、组织重塑和血管生成。本综述从受精开始，一直到早期妊娠结束，总结了当前的知识，因为这是胚胎最大损失的时期。结果表明，早期妊娠伴随着子宫内膜免疫细胞表达自然杀伤（CD335）细胞和细胞毒性 T 细胞（CD8）标志物的比例显著增加，同时表达主要组织相容性复合体 II 抗原（巨噬细胞和树突状细胞）的细胞增加。这伴随着早期妊娠子宫内膜中白细胞介素 15（一种自然杀伤细胞生长因子）和白细胞介素 10 的 mRNA 丰度增加。此外，与周期性小母牛相比，妊娠小母牛在第 17 天的吲哚胺 2,3 双加氧酶表达增加了 15 倍，但在第 20 天下降。这种酶将色氨酸转化为犬尿氨酸，通过造成局部色氨酸缺乏以及激活芳香烃受体和诱导下游耐受介质，改变免疫功能。芳香烃受体在牛子宫中表达丰富，但它在早期妊娠期间的时空调节尚未得到描述。妊娠还与已知抑制免疫激活的蛋白质表达增加有关，包括程序性细胞死亡配体 1（CD274）、淋巴细胞激活基因 3（CD223）和细胞毒性 T 淋巴细胞相关蛋白 4（CD152）。这些分子与抗原呈递细胞上的受体相互作用，并诱导淋巴细胞耐受。目前的结果支持这样的假设，即奶牛早期妊娠信号涉及子宫内膜中免疫细胞比例的变化，以及诱导已知介导耐受的分子。这些变化对于子宫壁重塑、胎盘形成和成功妊娠可能是必不可少的。
