Maternal Regulatory T cell antigen-specificity

母体调节性 T 细胞抗原特异性

• 批准号: 9174897
• 负责人: Sing Sing Way
• 金额: $ 39万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-05 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174897
• 关键词: Address; Agreement; Allogenic; Animals; Antigens; Autoantigens; Autoimmune Diseases; Biology; Birth; CD4 Positive T Lymphocytes; Cells; Disease remission; Engineering; Epidemiology; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Female; Fetus; Flow Cytometry; Fracture; Goals; Human; Immune; Immune Tolerance; Individual; Knowledge; Link; Maintenance; Memory; Microchimerism; Modeling; Mothers; Multiple Sclerosis; Mus; Normal tissue morphology; Organ; Peptides; Physiological; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Process; Property; Recurrence; Regulatory T-Lymphocyte; Research; Severity of illness; Specificity; Spontaneous abortion; Staining method; Stains; T-Cell Receptor; T-Lymphocyte; Tissues; Transgenic Mice; Work; base; cellular engineering; embryo/fetus antigen; experience; fetal; fetus cell; healthy pregnancy; in vivo; in vivo Model; innovation; magnetic beads; memory CD4 T lymphocyte; molecular phenotype; public health relevance; resilience; stillbirth; tool

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.

抽象。免疫耐受性扩大以适应发育中的小鼠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专门的免疫抑制剂， 母体CD4+ T细胞亚群，称为调节性T细胞（TCLs），而钝化母体Treg积累 发生在自然流产、先兆子痫和其他妊娠并发症与胎儿骨折有关 宽容这种对母体睾酮的需要在动物中得到加强，即使部分短暂的消耗 从扩大怀孕水平破坏胎儿耐受性和触发胎儿浪费。一个重要的，但 相对未表征的特征在于它们的抗原特异性。与其他T细胞一样， 具有确定的特异性，并且需要T细胞受体刺激来激活其抑制特性。 通过结合基于确定的特异性的用于追踪罕见的CD4+ T细胞的四聚体富集和使用 普遍表达确定的模型抗原的转基因小鼠在非转基因雌性中产生妊娠 将模型抗原转化为替代胎儿抗原，我们的初步研究表明， 具有胎儿特异性的母体T细胞扩增。通过在分娩后扩展该分析， 具有预先存在的胎儿特异性的母体T细胞，以及它们随着胎儿抗原再积累而更稳健的再积累， 在随后的怀孕中也显示了刺激。反过来，急剧增加的弹性对胎儿 与初次妊娠相比，第二次妊娠期间的浪费与胎儿数量的增加相吻合， 特定的内存容量。这些结果强调了母体Tibetan的潜在保护性记忆功能， 同意，并可能提供一个科学依据，以解释人类伴侣的具体保护利益的事先 成功怀孕，防止随后怀孕的并发症。然而，尽管有这种联系， 仍然未知的是胎儿特异性记忆T细胞是否能保护胎儿免于浪费。 解决这些关键的知识差距，需要新的策略，在体内操纵母体胸腺细胞 具有明确的胎儿特异性。我们的总体假设是，维持母体记忆TdR需要 胎儿细胞的持续刺激，在怀孕后的母亲体内建立微嵌合体。反过来， 微嵌合体胎儿细胞的存在使得记忆T细胞在保护胎儿免于在胚胎发育过程中浪费的必要性。 怀孕后要调查。此外，如果产后维持调节耐受性， 仅限于微嵌合胎儿细胞表达的抗原， 产后器官特异性自身免疫性疾病（如多发性硬化症）的快速复发可能反映了 胎儿微嵌合体细胞的组织限制性自身抗原表达不足。因此，实现 这些目标对于揭示Treg的基础生物学具有非常重要的意义， 记忆和抗原特异性，以及建立科学框架来解释流行病学 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。