Role of maternal Treg cells in the induction of neonatal tolerance

母体 Treg 细胞在诱导新生儿耐受中的作用

基本信息

批准号：
10213947
负责人：
Michiko Oyoshi
金额：
$ 21万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213947
关键词：
Adopted Adult Affect Allergens Allergic Anaphylaxis Animals Antibodies Antigen-Antibody Complex Atopic Dermatitis Basophils Birth Breast Feeding CD4 Positive T Lymphocytes Cells Child Chymase Dendritic Cells Development Disease Exhibits Extrinsic asthma Failure Fc Receptor Food Food Hypersensitivity Fostering Frequencies Gene Expression Gene Expression Profile Goals Health Human Human Milk ITGAX gene IgE Immune Immune response Immune system Immunoglobulin G Immunologic Factors Infant Intestines Investigation Life Mediating Mediator of activation protein Milk Mothers Mus Neonatal Oral Ovalbumin Pathogenicity Peripheral Phenotype Population Predisposition Proteins Public Health Regulatory T-Lymphocyte Role Serum Shapes Spleen Supplementation Time Tissues Work allergic response cytokine experimental study human data in vivo mast cell mouse model neonatal Fc receptor neonatal immune system neonate novel offspring perinatal period prevent response synergism tool

项目摘要

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.

项目概要食物过敏 (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) 细胞介导的耐受性在后代中的作用尚不清楚。我们最近发现母体对过敏原 [卵清蛋白 (OVA) 或花生] 的致敏可阻止小鼠后代的 FA 反应对相同过敏原的表皮致敏和口腔刺激的反应，如减少所示食物过敏反应、过敏原特异性免疫球蛋白 (Ig) E、血清小鼠肥大细胞蛋白酶 1 的水平，和肠道肥大细胞扩张。这种保护作用与 IgG 和 IgG 水平的增加有关。母乳中的过敏原免疫复合物 (IgG-IC)。新生儿 Fc 受体 (FcRn) 依赖性母体转移母乳中的 IgG-IC 和后代 CD11c+ 树突状细胞诱导的过敏原特异性 Treg 呈递 IgG-IC 后代细胞。 OVA 致敏母亲进行母乳喂养，或母亲 IgG-IC 补充引起新生儿耐受性。一致地，从非特应性母亲收集的母乳中含有 IgG-IC 和在人源化 FcRn 小鼠中诱导耐受。这些结果表明母体免疫因子，特别是 IgG- 母乳中的 IC 对于 Treg 细胞的诱导和控制新生儿的食物特异性耐受性至关重要。荒野- 由暴露于 OVA 的 Rag2-/- 母亲收养和喂养的 WT 型后代表现出对与 WT 对照相比，FA 与过敏原特异性 Treg 细胞频率的降低相关后代。暴露于 OVA 的 Rag2-/- 母亲补充 IgG-IC 未能挽救新生儿食物耐受性收养 WT 后代，表明 IgG-IC 需要额外的母乳因子才能成功诱导新生儿食物耐受性。人们已经认识到通过乳汁将母体细胞转移给婴儿关于母乳中 Treg 细胞的存在的描述很少。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脏中积累。母体 Treg 细胞的耗竭母乳喂养期间存在 IgG-IC 导致新生儿耐受失败。进一步，我们发现 Treg 细胞存在于人乳中。这些结果表明母体 Treg 通过乳汁转移具有在塑造新生儿免疫系统和对 FA 的易感性方面发挥着重要作用。本提案的目标目的是确定母乳中 Treg 细胞的表型，并破译这些细胞在调节中的作用新生儿的食物特异性耐受性。我们假设通过乳汁转移的母体 Treg 细胞发挥作用在围产期的特定时间窗口内与母体转移的过敏原（IgG-IC）协同作用，成功诱导新生儿食物耐受。我们还假设母乳 Treg 细胞表现出独特的与全身 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的改变后代中 FA 的变化反映了抑制性 Treg 细胞表型的失调。