Maternal Regulatory T cell antigen-specificity

抽象的。免疫耐受性扩大以适应发育中表达的外来父系抗原 怀孕期间的胎儿。这一重要过程需要持续扩大一种专门的免疫抑制药 母体CD4+T细胞亚群，称为调节性T细胞(Tregs)，而迟钝的母体Treg蓄积 发生在自然流产、先兆子痫和其他与胎儿骨折有关的妊娠并发症中 宽容。这种对母体树突状细胞的必要性在动物身上得到了加强，即使是部分短暂的衰竭 来自扩大的妊娠水平会扰乱胎儿的耐受性，并引发胎儿损耗。有一点很重要，但是 Tregs相对不具特征的特征在于其抗原特异性。像其他T细胞一样，单个树突状细胞 有明确的特异性，需要刺激T细胞受体来激活它们的抑制特性。 通过结合四聚体浓缩来追踪基于确定的特异性的稀有CD4+T细胞和使用 在非转基因雌性中普遍表达特定模型抗原以父系怀孕的转基因小鼠 将模型抗原转化为替代胎儿抗原，我们的初步研究表明怀孕素数很强 具有胎儿特异性的母系树的扩大。通过在分娩后扩展这一分析，维持 具有预先存在的胎儿特异性的母体Tregs，以及它们与胎儿抗原重新聚集更强劲的再聚集 随后怀孕时的刺激作用也被揭示出来。反过来，大幅提高了对胎儿的弹性 与初次妊娠相比，二次妊娠期间的损耗与扩大的胎儿池相吻合- 特定的内存树。这些结果强调了母体树的潜在保护性记忆特征 并可提供科学依据来解释人类伴侣特定的保护利益 成功怀孕，防止再次怀孕时出现并发症。尽管如此，尽管有这种联系， 目前尚不清楚的是，胎儿特有的记忆树是否提供了防止胎儿萎缩的保护作用。 解决这些关键的知识差距需要新的策略在体内操纵母体树突状细胞 具有明确的胎儿特异性。我们的总体假设是，维持母体记忆树需要 胎儿细胞持续刺激，在怀孕后在母亲体内建立微嵌合体。反过来，枯竭 对微嵌合胎儿细胞的研究允许记忆树的必要性，以防止在 晚些时候的怀孕情况有待调查。此外，如果产后维持调节耐受性是 仅限于微嵌合胎儿细胞表达的抗原，短暂妊娠诱导的缓解和 器官特异性自身免疫性疾病(如多发性硬化症)产后迅速复发可能反映了 胎儿微嵌合体细胞自身抗原表达不足。因此，完成 这些目标对于解开Treg的基础生物学具有极其重要的意义 记忆和抗原特异性，以及建立解释流行病学的科学框架 人类妊娠并发症的特征和分娩后自身免疫性疾病严重程度的变化。

Abstract. Immune tolerance expands to accommodate foreign paternal antigens expressed by the developing fetus during pregnancy. This vital process requires sustained expansion of a dedicated immune suppressive maternal CD4+ T cell subset, called regulatory T cells (Tregs), whereas blunted maternal Treg accumulation occurs in spontaneous abortion, preeclampsia and other pregnancy complications linked with fractured fetal tolerance. This necessity for maternal Tregs is reinforced in animals where even partial transient depletion from expanded pregnancy levels disrupts fetal tolerance and triggers fetal wastage. One important, but relatively uncharacterized feature of Tregs lies in their antigen specificity. Like other T cells, individual Tregs have defined specificity, and T cell receptor stimulation is required for activating their suppressive properties. By combining tetramer enrichment for tracking rare CD4+ T cells based on defined specificity and the use of transgenic mice that ubiquitously express defined model antigens to sire pregnancy in non-transgenic females that transforms model antigens into surrogate fetal antigens, our initial studies show pregnancy primes robust expansion of maternal Tregs with fetal specificity. By extending this analysis after parturition, maintenance of maternal Tregs with pre-existing fetal specificity, and their more robust re-accumulation with fetal-antigen re- stimulation in subsequent pregnancies were also revealed. In turn, sharply increased resiliency against fetal wastage during secondary compared with primary pregnancy coincides with this expanded pool of fetal- specific memory Tregs. These results highlighting potential protective memory features for maternal Tregs are in agreement, and may provide a scientific basis to explain human partner-specific protective benefits of prior successful pregnancy against complications in subsequent pregnancies. Nonetheless, despite this association, what remains unknown is whether fetal-specific memory Tregs confer protection against fetal wastage. Addressing these critical gaps in knowledge require new strategies for in vivo manipulation of maternal Tregs with defined fetal specificity. Our overall hypothesis is that maintenance of maternal memory Tregs requires ongoing stimulation by fetal cells that establish microchimerism in mothers after pregnancy. In turn, depletion of microchimeric fetal cells allows the necessity of memory Tregs in protection against fetal wastage during later pregnancies to be investigated. Furthermore, if postpartum maintenance of regulatory tolerance is restricted to antigens expressed by microchimeric fetal cells, the transient pregnancy-induced remission and swift postpartum recurrence of organ-specific autoimmune disorders (e.g. multiple sclerosis) may reflect inadequate expression of tissue restricted self antigens by fetal microchimeric cells. Therefore, accomplishing these aims are of exceptionally high significance for unraveling the fundamental biology of Treg with regards to memory and antigen-specificity, as well as establishing the scientific framework to explain epidemiological features of human pregnancy complications and shifts in autoimmune disease severity after parturition.