2. 西南大学动物科技学院, 重庆 400715
2. College of Animal Science and Technology, Southwest University, Chongqing 400715, China
子宫自然杀伤(uterine natural killer, uNK)细胞是哺乳动物生理周期分泌阶段和妊娠早中期子宫内数量最多的免疫细胞。哺乳动物妊娠早期，子宫蜕膜中约40%为淋巴细胞，而其中70%左右淋巴细胞为NK细胞[1]。妊娠后期，uNK细胞数量却呈现下降趋势，下降到妊娠前水平。与外周NK细胞(CD56dimCD16+)表型不同，uNK细胞表型为CD56brightCD16-，具有未成熟NK细胞的特征，以及高表达抑制性受体，杀伤功能下降，分泌能力增强等特点[2-4]。研究发现，uNK细胞不仅在宫内抗感染方面发挥作用，在建立子宫内免疫耐受环境、促进胎盘和胎儿发育等过程中也具有重要的调控作用[5-6]。那么，妊娠期间uNK细胞活性受何种因素调控？uNK细胞又是通过何种调节机制平衡子宫内维持免疫耐受与抵抗病原感染[7-8]？目前有关uNK细胞活性调控机制方面的研究非常匮乏，因此，本文综合相关研究，首先详细介绍uNK细胞在建立母-胎免疫耐受环境，促进胎盘和胎儿发育等方面的最新进展，并综合激素、糖代谢以及DNA甲基化等对外周和其他组织中NK细胞的调控研究概况，为深入开展妊娠中uNK细胞活性调控机制研究提供新的研究方向和思路，为开发新的生殖调控、癌症治疗以及移植排斥手段提供可借鉴的参考依据。
1 uNK细胞对母-胎免疫耐受环境的影响妊娠是一个复杂的生理过程，母-胎界面的免疫状态决定了与母体只有一半基因型相同的胚胎能否成功定植以及正常发育[9]。妊娠早中期，母-胎界面中免疫细胞主要由自然杀伤细胞、巨噬细胞、T细胞以及树突状细胞组成，而其中NK细胞是数量最多的免疫细胞(70%左右)，uNK细胞对母-胎免疫耐受环境的建立起到至关重要的调控作用[10]。
妊娠期，母-胎界面存两种形式的免疫互作关系：第一种形式是uNK细胞直接与滋养层细胞以及子宫基质细胞之间对话。uNK细胞表面的杀伤细胞免疫球蛋白样受体(killer cell immunoglobulin-like receptor, KIR)与胎儿滋养层细胞表达的独特HLA-G分子结合后，启动细胞内抑制性信号通路，抑制其杀伤活性，而增强其白细胞介素8(IL-8)、干扰素诱导蛋白10(IP-10)等因子的分泌表达，避免对滋养层细胞损伤，促进其侵袭[11-13]。当滋养层细胞的miR-133a下调HLA-G表达后，直接抑制uNK细胞分泌功能，导致自身侵袭障碍，引起流产的发生[14-15]。胚胎定植过程中，uNK细胞通过子宫内聚集以及表达细胞因子IL-25促进子宫内皮基质细胞(ESCs)分化为蜕膜基质细胞(DSCs)[16]。因此，uNK细胞与滋养层细胞之间有效的互作关系，是胎盘和胚胎在子宫内正常发育的前提条件。第二种形式是uNK细胞与蜕膜中其他免疫细胞相互作用。蜕膜巨噬细胞通过分泌转化生长因子β(TGF-β)可以减弱uNK细胞的杀伤能力[17]，而uNK细胞通过大量分泌IFN-γ抑制Th17极化，抑制子宫局部炎症反应，为建立母-胎界面的免疫耐受环境创造了必要的条件。但在反复流产病人蜕膜组织中uNK细胞比例明显下降，分泌IFN-γ减少，而Th17细胞大量浸润，IL-6和IL-1β等促炎因子大量表达[18-19]，此外，uNK细胞通过分泌半乳糖凝集素-1(galectin-1)与蜕膜中CD3+T细胞膜上高亲和力的聚乙酰氨基内酯结合，启动蜕膜中CD3+T细胞凋亡[20]，导致胎儿不能正常定植发育。由此可见，uNK细胞在建立母-胎免疫耐受过程中起到关键的作用，受到胎盘滋养层细胞HLA-G分子刺激后，一方面通过降低自身杀伤能力保证胚胎顺利定植，另一方面通过调节其他免疫细胞活性为母-胎免疫耐受环境的维持创造条件。
2 uNK细胞对胎盘和胎儿发育的影响妊娠早期，uNK细胞大量聚集于子宫蜕膜，分布于螺旋动脉周围[21]，通过促进螺旋动脉的形成发挥对胎盘早期发育的调控作用。uNK细胞通过分泌细胞因子、生长因子以及蛋白酶(如金属基质蛋白酶MMP-2)等，促进滋养层细胞侵袭和螺旋动脉的重塑，为胎盘的发育形成提供必要的前提条件[22]。研究显示，小鼠孕早期螺旋动脉重塑时间与uNK细胞分泌IFN-γ的峰值时间重合，而敲除IFN-γ基因的孕鼠则出现螺旋动脉重塑异常，IFN-γ能够瓦解蜕膜动脉血管壁的完整性，使得动脉内皮和平滑肌细胞结构松散，利于滋养层细胞入侵，完成螺旋动脉重塑[23]。除IFN-γ外，人uNK细胞还分泌表达促血管生成素(Ang)、转化生长因子β1(TGF-β1)和血管内皮生长因子(VEGF)等多种细胞因子，促进螺旋动脉形成[24-26]。
妊娠过程中，胎儿发育同样受到uNK细胞活性的影响。Fu等[27]研究发现，小鼠uNK细胞能够分泌多种促生长因子如骨诱导因子(osteoglycin)、多效生长因子(pleiotrophin)，保证胎儿的正常发育；敲除小鼠uNK细胞转录因子Nfi13，则降低其分泌促生长因子能力，引起类似于老龄妊娠而导致的胎儿数量减少和胎儿发育受限的症状(图 1)；相反，在老龄小鼠妊娠早期，通过移植正常uNK细胞，则可以重建子宫内环境，逆转胎儿生长受限，保证胎儿正常发育。
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图 1 uNK细胞活性影响胎儿发育示意图[9] Fig. 1 Schematic diagram of uNK cell activity affecting fetal development[9] |
近年研究结果表明，uNK细胞不仅在胚胎定植、胎盘发育、螺旋动脉重塑以及胎儿发育等过程中发挥了重要的调控作用，而且在病毒感染过程中仍然发挥免疫抗感染作用，避免胎盘及胎儿受到病毒侵害。因此，以免疫学为理论，以调控uNK细胞活性为方向，开发调控人类高龄妊娠以及促进生产动物多胎繁殖的新技术，将会成为生殖免疫研究的新趋势。
3 uNK细胞生物活性调控机制妊娠过程中，uNK细胞既要抑制杀伤能力为胚胎发育创造免疫耐受环境，另一方面仍要保持对病毒等病原微生物的抗感染作用，以保证妊娠过程中不受病原的侵袭。那么，uNK细胞活性是通过何种方式进行活性调控以维持二者之间平衡，保证妊娠正常进行呢？虽然，目前有关uNK细胞活性调控机制的研究并不多，但激素、糖代谢以及表观遗传等对外周血和其他组织中NK细胞生物活性的调控机制研究，为深入探索妊娠过程中uNK细胞的调控机制提供了可借鉴的研究思路。
3.1 性激素水平对NK细胞活性的影响妊娠过程中，子宫内激素水平发生改变，这些激素直接或间接作用于uNK细胞，显著影响子宫内免疫状态[10, 28]。如黄体酮促进体外培养的子宫内膜基质细胞表达IL-15能力增强，而IL-15是uNK细胞分化增殖的强效细胞因子[29]。卵巢切除的小鼠，注射17β-雌二醇2 h后，即可发现uNK细胞在子宫内膜层小血管周围募集，并随着激素水平下降而逐渐消退；注射孕酮12 h后，uNK细胞在子宫内膜小血管内皮细胞处大量募集[30]。将山羊uNK细胞与子宫内膜基质细胞(ESC)共培养时，雌激素E2单独或与孕酮P4共同作用可显著抑制uNK细胞分泌VEGF和IFN-γ[31-32]。米非司酮作为黄体酮的强效拮抗剂，常被用于抗孕使用，人uNK细胞体外培养过程中添加1.0 μmol·L-1非米司酮后，细胞杀伤活性和穿孔素表达水平都有显著的提高[33]。雌性动物子宫具有平衡免疫保护和满足生殖的功能，此功能受到多种性激素周期性影响，在维持子宫动态平衡过程中，uNK细胞生物活性受哪些性激素精准调控，其具体调控机制尚未明确。笔者认为，研究性激素调控uNK细胞活性过程中，应建立与妊娠过程中子宫内性激素水平相同的培养环境，明确在妊娠不同阶段不同性激素水平改变过程中，uNK细胞活性改变情况，并进一步揭示其参与相关分子及信号通路的作用机制。
3.2 糖代谢过程对NK细胞活性的调节糖代谢过程为免疫细胞生命活动提供必要的能源[34-35]，糖代谢状态改变引起免疫细胞活性变化，而处于不同状态的免疫细胞其代谢状态也存在差异[36-40]。NK细胞是机体主要抗肿瘤免疫细胞，在肺癌起始阶段向促进和扩散阶段发展过程中，由于肺组织中NK细胞的果糖-1, 6-双磷酸酶(FBP1)表达升高，抑制其糖酵解，引起NK细胞杀伤活性减弱和数量减少，导致肺癌细胞免疫逃避，引起肺癌恶化[41]。黑色素瘤患者体内乳酸脱氢酶(LDHA)表达升高，乳酸不断积累从而抑制NK细胞核因子活化和IFN-γ分泌表达，导致免疫监视能力下降，预示其预后不良[42]。白细胞介素15(IL-15)是NK细胞的强效激活剂[43]，利用其刺激体外培养NK细胞时，与CDdimNK细胞相比，CD56brightNK细胞表达更多葡萄糖转运蛋白Glut1，表现出更强的葡萄糖吸收能力，而其糖酵解过程被抑制则会显著影响其IFN-γ分泌表达[44-45]。妊娠过程中，大量增殖的胎盘滋养层细胞和uNK细胞之间的互作关系与癌细胞和NK细胞关系非常相似，那么uNK细胞数量动态变化是否也涉及糖代谢功能改变？采用单细胞转录组测序方法，对采集的妊娠6~14周人蜕膜组织以及外周血共70 000个细胞进行分析，结果表明，妊娠早期高表达HLA-G受体的uNK细胞中参与糖酵解过程的多个酶呈现高表达状态[46]，此研究结果提示，uNK细胞生物活性可能受到糖代谢的调节。妊娠过程中，母-胎界面滋养层细胞大量增殖会消耗氧气，造成局部低氧环境，进而影响细胞糖代谢功能。研究uNK细胞糖代谢调控作用过程，既要考虑低氧环境引起细胞本身糖代谢改变，也要认识到周围其他细胞如滋养层细胞糖代谢产物对其活性的影响。目前，细胞代谢在癌细胞中的研究比较深入，而uNK细胞糖代谢相关研究则较少，从糖代谢角度揭示妊娠过程中uNK细胞独特的生物活性调控机制将成为新的探索方向。
3.3 DNA甲基化对NK细胞功能的调控DNA甲基化是一种重要的表观遗传修饰，在各类免疫细胞基因表达调控过程中发挥重要作用[47-50]。哺乳动物中，DNA甲基化主要发生在胞嘧啶的5位点，位点形成5-甲基胞嘧啶(5mC)，5mC在体内处于动态变化，可通过主动或复制依赖的被动方式去甲基化，进而调控基因表达[51-52]。Ezh2是一种组蛋白甲基转移酶，将其敲除或抑制后，造血干细胞表达白细胞介素-15受体(CD122)和NKG2D活化受体增加，更多的分化成熟为NK细胞[53]。NK细胞分化过程中，IFNG启动子通过去甲基化的表观重塑方式活化，分泌表达更多的IFN-γ[54-55]。NK细胞内KIR基因在表达过程中其转录起始部位CpG岛持续低甲基化；通过DNA去甲基化处理，则可诱导NK细胞中KIR基因表现出快速和稳定的转录和表达[56-58]。5-氮胞苷是一种甲基化抑制剂，将其添加在NK-92MI细胞系培养液中进行去甲基化处理，可以抑制NK-92MI细胞的杀伤活力[59]。以上研究结果表明，DNA甲基化对NK细胞的分泌表达和杀伤力起到重要的表观调控作用。
近年研究发现，急性髓性白血病患者的MLL基因的融合蛋白——双加氧酶TET1(ten-eleven translocation 1)具有催化5甲基胞嘧啶(5mC)转化为5羟甲基胞嘧啶(5hmC)的作用[60-61]。现已证实，双加氧酶TET1是真核细胞重要的DNA去甲基化酶，在胚胎发育[62-64]、癌症发生[65-66]、细胞重排[67-69]以及免疫细胞分化、增殖表达[70-72]等过程中起到重要表观调控作用。TET1基因敲除雌性小鼠与正常雄鼠交配后，出现产子数下降和后代体弱等情况[64, 73]。雌鼠因缺失双加氧酶TET1表现出产子数下降和后代体弱的表型与雌鼠体内uNK细胞数量减少造成的繁殖缺陷非常相似。妊娠期间，人、小鼠、羊等多种动物胎盘中双加氧酶TET1的表达动态模式[74-76]与uNK细胞数量变化趋势非常相似。笔者认为，TET1极有可能通过去甲基化作用调控uNK细胞生物活性，因此，以双加氧酶TET1为起点，研究uNK细胞的表观调控作用，是全面阐明uNK细胞活性调控机制的重要组成。
4 小结与展望目前，虽有人工辅助生殖技术，如胚胎移植、人工授精等可以帮助人类受孕和提高饲养动物繁殖生产。但习惯性流产、病原性繁殖障碍症以及胎儿发育受限等妊娠性疾病仍是阻碍人类和其他哺乳动物正常妊娠的重要因素。而uNK细胞作为妊娠早中期数量最多的免疫细胞，对维持母-胎免疫耐受环境，调节螺旋动脉重塑，促进胎盘和胎儿的正常发育以及子宫内抗感染等起到至关重要的调控作用。笔者认为，通过调节uNK细胞活性或补充uNK细胞数量治疗或预防人类和动物的繁殖障碍性疾病，将会成为今后生殖免疫调控研究的新方向。另外，滋养层细胞与癌细胞的生物活性非常相似，尤其在抗原性和侵袭性方面，而uNK细胞与滋养层细胞之间的互作关系，可以作为癌症和器官移植等研究的生物模型，进而研究癌症免疫逃避以及器官移植排斥的相关机制，建立以调节NK细胞活性为主要手段的免疫治疗方法。
近年研究发现，DNA甲基化、组蛋白乙酰化以及葡萄糖代谢等参与多种免疫细胞如T细胞、树突状细胞、巨噬细胞的活性调控过程。结合妊娠过程中子宫内环境特点，通过表观遗传组学和细胞代谢组学方法，深入研究uNK细胞的调控机制必将成为生殖免疫和细胞免疫研究的新方向。在不同细胞发挥生理功能的过程中，激素、葡萄糖代谢以及表观遗传因素之间相互调控，如某些激素具有调控细胞葡萄糖代谢作用[77-78]，葡萄糖相关产物能够活化表观遗传调控因子活性[79-81]，而表观遗传调控因子则可参与相关激素活性作用过程[82]。值得注意的是，妊娠过程中，母-胎界面环境非常复杂，既存在各种激素水平的变化，同时也存在大量细胞增殖代谢造成局部环境的改变，因此，uNK细胞可能受到激素、细胞代谢以及表观遗传等多因素的网络调控，笔者认为，在研究激素、细胞代谢和表观遗传等对uNK细胞活性调控时，应注意综合分析不同因素作用的交叉性，全面准确阐明uNK细胞调控机制，为通过调控uNK细胞活性来发展生殖调控和肿瘤治疗新技术提供依据。
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