Zenclussen Ana C, Gerlof Katrin, Zenclussen Maria L, Ritschel Stefanie, Zambon Bertoja Annarosa, Fest Stefan, Hontsu Shigeto, Ueha Satoshi, Matsushima Kouji, Leber Joachim, Volk Hans-Dieter
Institute of Medical Immunology, Charité, Medical University Berlin, Berlin, Germany.
Eur J Immunol. 2006 Jan;36(1):82-94. doi: 10.1002/eji.200535428.
The mechanisms underlying immune tolerance during pregnancy are poorly understood. In this regard, Treg seem to play an important role in mediating maternal tolerance to the fetus. We proposed a crucial role of T regulatory cells (Treg) in avoiding immunological rejection of the fetus after observing diminished number and function of Treg in abortion-prone mice. We further confirmed the protective role of Treg during pregnancy by transferring pregnancy-induced Treg into abortion-prone mice, which prevented rejection. Here, we analyzed the mechanisms involved in Treg-mediated protection. As expected, Treg therapy prevented abortion, while expanding the peripheral and thymic Treg population. Surprisingly, the decidual levels of the Th1 cytokines IFN-gamma and TNF-alpha were not diminished after therapy. Interestingly, the mRNA levels of leukemia inhibitory factor, TGF-beta and heme oxygenase-1 at the fetal-maternal interface were dramatically up-regulated after Treg transfer, while the levels of indolamine 2,3-dioxygenase remained unchanged. Our data suggest that Treg treatment can not prevent T cell infiltration or high Th1 levels but is able to create a privileged tolerant microenvironment at the fetal-maternal interface, further shedding light onto the molecular mechanisms involved in pregnancy tolerance.
孕期免疫耐受的潜在机制目前仍知之甚少。在这方面，调节性T细胞（Treg）似乎在介导母体对胎儿的耐受性中发挥重要作用。在观察到易流产小鼠体内Treg数量减少和功能降低后，我们提出了调节性T细胞（Treg）在避免胎儿免疫排斥方面的关键作用。我们通过将妊娠诱导的Treg转移到易流产小鼠体内，进一步证实了Treg在孕期的保护作用，这预防了排斥反应。在此，我们分析了Treg介导的保护作用所涉及的机制。正如预期的那样，Treg疗法预防了流产，同时增加了外周和胸腺Treg群体。令人惊讶的是，治疗后蜕膜中Th1细胞因子IFN-γ和TNF-α的水平并未降低。有趣的是，Treg转移后，胎儿-母体界面处白血病抑制因子、转化生长因子-β和血红素加氧酶-1的mRNA水平显著上调，而吲哚胺2,3-双加氧酶的水平保持不变。我们的数据表明，Treg治疗不能阻止T细胞浸润或降低Th1水平，但能够在胎儿-母体界面创造一个特殊的耐受微环境，进一步揭示了妊娠耐受所涉及的分子机制。
