Tim-3 signaling in peripheral NK cells promotes maternal-fetal immune tolerance and alleviates pregnancy loss
Tim-3 signaling in peripheral NK cells promotes maternal-fetal immune tolerance and alleviates pregnancy loss
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外周 NK 细胞中的 Tim-3 信号传导可促进母胎免疫耐受并减轻流产
DOI：
10.1126/scisignal.aah4323
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发表时间：
2017-09-26
影响因子：
7.3
通讯作者：
Du, Meirong
中科院分区：
文献类型：
--
作者：
Li, Yanhong;Zhang, Jiayuan;Du, Meirong
约15%的临床确认妊娠发生妊娠丢失，而母胎免疫耐受缺陷导致超过50%的这些事件。我们发现，I型膜蛋白T细胞免疫球蛋白和含粘蛋白蛋白3（Tim-3）在自然杀伤（NK）细胞的信号传导在妊娠早期具有重要的保护作用。在妊娠早期，外周血NK细胞（pNK细胞）上的Tim-3瞬时大量增加，这依赖于白细胞介素-4（IL-4）-信号转导子和转录激活子6（STAT 6）和孕酮信号转导。Tim-3（+）pNK细胞显示免疫抑制活性，包括产生抗炎细胞因子和以转化生长因子β 1（TGF-β 1）依赖性方式诱导调节性T细胞（T-NK）。pNK细胞上的Tim-3被其配体半乳糖凝集素-9（Gal-9）刺激，导致通过激酶c-Jun N-末端激酶（JNK）和AKT的信号传导。在复发性流产（RM）患者中，pNK细胞上的Tim-3丰度降低，Tim-3（+）pNK细胞的免疫抑制活性受损。与来自正常妊娠供体的Tim-3（+）pNK细胞相比，RM患者Tim-3（+）pNK细胞在某些遗传基因座中表现出DNA可接近性的变化，这通过抑制可接近的染色质阅读蛋白而逆转。此外，Tim-3（+）pNK细胞，而不是Tim-3-pNK细胞，减少流产倾向和NK细胞缺陷小鼠的胎儿丢失。总之，我们的研究结果揭示了Tim-3-Gal-9信号转导介导的免疫调节pNK细胞在母胎免疫耐受中的关键作用，并表明pNK细胞上的Tim-3丰度是RM诊断的潜在生物标志物。
Pregnancy loss occurs in about 15% of clinically recognized pregnancies, and defective maternal-fetal immune tolerance contributes to more than 50% of these events. We found that signaling by the type I membrane protein T cell immunoglobulin and mucin-containing protein 3 (Tim-3) in natural killer (NK) cells had an essential protective role during early pregnancy. Tim-3 on peripheral NK (pNK) cells was transiently increased in abundance during the first trimester of pregnancy, which depended on interleukin-4 (IL-4)-signal transducer and activator of transcription 6 (STAT6) and progesterone signaling. Tim-3(+) pNK cells displayed immunosuppressive activities, including the production of anti-inflammatory cytokines and the induction of regulatory T cells (T-regs) in a transforming growth factor-beta 1 (TGF-beta 1)-dependent manner. Tim-3 on pNK cells was stimulated by its ligand galectin-9 (Gal-9), leading to signaling by the kinases c-Jun N-terminal kinase (JNK) and AKT. In recurrent miscarriage (RM) patients, Tim-3 abundance on pNK cells was reduced and the immunosuppressive activity of Tim-3(+) pNK cells was impaired. Compared to Tim-3(+) pNK cells from donors with normal pregnancies, RM patient Tim-3(+) pNK cells exhibited changes in DNA accessibility in certain genetic loci, which were reversed by inhibiting accessible chromatin reader proteins. Furthermore, Tim-3(+) pNK cells, but not Tim-3-pNK cells, reduced fetal loss in abortionprone and NK cell-deficient mice. Together, our findings reveal a critical role for Tim-3-Gal-9 signaling-mediated immunoregulation by pNK cells in maternal-fetal immune tolerance and suggest that Tim-3 abundance on pNK cells is a potential biomarker for RM diagnosis.