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

• 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
• 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

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.

项目摘要 食物过敏（FA）是一个日益增长的公共卫生问题。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知之甚少。我们最近发现， 母体过敏原[卵清蛋白（OVA）或花生]可阻止小鼠后代的FA反应， 对相同变应原的表皮致敏和口服激发的反应，如降低所示 在食物过敏反应、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 和肠肥大细胞的扩张。这种保护与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IgG-IC和子代CD 11 c+树突状细胞诱导的IgG-IC呈递 细胞在后代。OVA致敏母亲的母乳喂养，或母体IgG-IC补充诱导 新生儿耐受性一致地，从非特应性母亲收集的人母乳含有IgG-IC， 在人源化FcRn小鼠中诱导耐受性。这些结果表明，母体免疫因素，特别是IgG- 母乳中的IC对于诱导Treg细胞和控制新生儿的食物特异性耐受性至关重要。狂野- 由暴露于OVA的Rag 2-/-母亲收养和喂养的WT型后代显示对 FA与WT对照相比，与过敏原特异性Treg细胞的频率降低相关。 后代暴露于OVA的Rag 2-/-母亲补充IgG-IC未能挽救新生儿的食物耐受性， 采用WT后代，表明IgG-IC需要额外的母乳因子才能成功诱导 新生儿食物耐受性已经认识到通过乳汁将母体细胞转移给婴儿，然而， 母乳中存在母体Treg细胞的描述很少。我们发现母体Treg细胞被转移到 通过乳汁传给后代，并在后代的肠和脾脏中积累。母体Treg细胞耗竭 在母乳喂养期间，在IgG-IC的存在下，导致新生儿耐受失败。此外，我们发现 Treg细胞存在于母乳中。这些结果表明，通过乳汁的母体Treg转移具有显著的免疫调节作用。 在塑造新生儿免疫系统和对FA的易感性方面起着重要作用。本提案的目标 是建立乳汁中母体Treg细胞的表型并破译这些细胞在调节中的作用 新生儿的食物耐受性。我们假设通过乳汁转移的母体Treg细胞在哺乳动物中起作用， 在围产期的特定时间窗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 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的增加反映了抑制性Treg细胞表型的失调。