Role of maternal Treg cells in the induction of neonatal tolerance

项目摘要 食物过敏(FA)是一个日益严重的公共卫生问题。母体免疫反应对诱导的影响 调节性T(Treg)细胞在后代中介导的耐受的机制还知之甚少。我们最近发现， 母鼠变应原[卵清蛋白(OVA)或花生]致敏可阻止子代的FA反应 对皮肤表面致敏和口服相同过敏原的反应，如下降所示 在食物过敏反应、变应原特异性免疫球蛋白(Ig)E、血清肥大细胞蛋白酶1、 和肠道肥大细胞的扩张。这种保护与免疫球蛋白和免疫球蛋白水平的增加有关 母乳中的过敏原免疫复合物(Ig G-IC)。新生儿Fc受体(FcRN)依赖的母体移植 母乳免疫球蛋白IC及子代CD11c+树突状细胞诱导的过敏原特异性Treg 后代体内的细胞。卵清蛋白致敏母亲的母乳喂养或母亲补充免疫球蛋白 新生儿耐受性。始终如一地，从非特应性母亲那里收集的人类母乳中含有免疫球蛋白IC和 人源化FcRN小鼠的耐受诱导。这些结果表明，母体免疫因素，尤其是免疫球蛋白- 母乳中的IC对于诱导Treg细胞和控制新生儿对食物的耐受性至关重要。狂野的- 由OVA暴露的Rag2-/-母亲收养和哺育的WT型后代对 与WT对照组相比，FA与WT对照组相比，与过敏原特异性Treg细胞频率降低有关 后代。补充OVA暴露的Rag2-/-母亲的Ig-IC未能挽救新生儿的食物耐受性 领养的WT后代，表明Ig G-IC需要额外的母乳因素才能成功诱导 新生儿食物耐受性。母体细胞通过牛奶转移给婴儿已经被认识到了，然而， 母乳中存在母体Treg细胞的描述很少。我们发现母体Treg细胞被转移 通过乳汁传给后代，并在后代的肠道和脾中积累。母体Treg细胞的耗竭 在母乳喂养期间，新生儿在免疫球蛋白-IC存在的情况下耐受性失败。此外，我们发现， 母乳中存在Treg细胞。这些结果表明，母体Treg通过母乳转移具有 在塑造新生儿免疫系统和对FA的易感性方面具有重要作用。这项提案的目标是 目的是建立母乳中母体Treg细胞的表型，并破译这些细胞在调节 新生儿的食物特异性耐受性。我们假设通过母乳转移的母体Treg细胞在 在围产期的特定时间窗内与母源转移变应原(Ig G-IC)的协同作用 成功诱导新生儿食物耐受。我们还假设母体乳汁Treg细胞表现出独特的 与系统性Treg细胞相比的表型和基因表达谱。最后，我们假设 母乳Treg细胞表现出与发育相关的基因表达谱变化 这反映了抑制性Treg细胞表型的失调。

Project Summary Food allergy (FA) is a growing public health concern. The effects of maternal immune responses on the induction of regulatory T (Treg) cell-mediated tolerance in offspring are poorly understood. We have recently found that maternal sensitization with allergen [ovalbumin (OVA) or peanut] prevented FA responses in murine offspring in response to epicutaneous sensitization and oral challenge with the same allergen, as indicated by a decrease in the levels of food anaphylaxis, allergen-specific immunoglobulin (Ig) E, serum mouse mast cell proteinase 1, and intestinal mast cell expansion. This protection was associated with an increase in the levels of IgG and allergen immune complexes (IgG-IC) in breast milk. Neonatal Fc receptor (FcRn)-dependent transfer of maternal IgG-IC via breast milk and IgG-IC presentation by offspring CD11c+ dendritic cells induced allergen-specific Treg cells in offspring. Breastfeeding by OVA-sensitized mothers, or maternal IgG-IC supplementation induced neonatal tolerance. Consistently, human breast milk collected from non-atopic mothers contained IgG-IC and induced tolerance in humanized FcRn mice. These results indicate that maternal immune factors, especially IgG- IC, in breast milk are critical for the induction of Treg cells and control food-specific tolerance in neonates. Wild- type (WT) offspring adopted and nursed by OVA-exposed Rag2-/- mothers showed failure of tolerance towards FA as compared to WT controls, associated with a decrease in the frequencies of allergen-specific Treg cells in offspring. IgG-IC supplementation of OVA-exposed Rag2-/- mothers failed to rescue neonatal food tolerance in adopted WT offspring, suggesting that IgG-IC require additional maternal milk factors to successfully induce neonatal food tolerance. Transfer of maternal cells to infants through milk has been recognized, however, the presence of maternal Treg cells in milk are poorly described. We found that maternal Treg cells were transferred to offspring via milk and accumulated in the intestine and spleen of offspring. Depletion of maternal Treg cells during breastfeeding period resulted in failure of neonatal tolerance in the presence of IgG-IC. Further, we found that Treg cells are present in human milk. These results suggest that maternal Treg transfer via milk has a significant role in shaping the neonatal immune system and the susceptibility to FA. The goals of this proposal are to establish the phenotype of maternal Treg cells in milk and to decipher the role of these cells in regulating food-specific tolerance in neonates. We hypothesize that maternal Treg cells transferred through milk act in synergy with maternally transferred allergens (IgG-IC) during a specific time window in the perinatal period to successfully induce neonatal food tolerance. We also hypothesize that maternal milk Treg cells exhibit unique phenotype and gene expression profiles as compared to systemic Treg cells. Lastly, we hypothesize that maternal milk Treg cells exhibit alterations in gene expression profiles that are associated with the development of FA in offspring that reflect a dysregulation of the suppressive Treg cell phenotype.