Development and significance of the plasma cell niche in the human infant thymus

人类婴儿胸腺浆细胞生态位的发育和意义

• 批准号: 10265678
• 负责人: Emmanuel Zorn
• 金额: $ 39.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265678
• 关键词: ABO blood group system; Adoptive Transfer; Age; Animals; Antibodies; Antibody-Producing Cells; Antigens; Architecture; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Bacterial Antigens; Biological; Birth; Blood; Blood Group Antigens; Bone Marrow; Cell Survival; Cells; Child Health; Clone Cells; Collection; Dangerousness; Development; Exposure to; Fibrous capsule of kidney; Flow Cytometry; Frequencies; Gene Expression Profiling; Generations; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunization; Immunize; Immunochemistry; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulins; Individual; Infant; Infection; Kinetics; Knowledge; Life; Maintenance; Maternal antibody; Memory; Memory B-Lymphocyte; Modeling; Molecular Cloning; Molecular Profiling; Mouse Strains; Mus; Nature; Peripheral; Phenotype; Plasma Cells; Population; Reactive Plasma Cell; Research; Role; Series; Serology; Serum; Specimen; Spleen; T-Lymphocyte; Thymus Gland; Time; Vaccinated; Vaccination; Vaccine Design; Viral; Viral Antigens; Virus; aged; base; chemokine receptor; cohort; dynamical evolution; experience; food antigen; improved; migration; next generation sequencing; pathogen; plasma cell differentiation; postnatal period; secondary lymphoid organ; thymus transplantation

Project Summary Our preliminary studies revealed the dynamic evolution of B cell subsets as a function of age in the human thymus. An initial contingent of medullary B cells present at birth and displaying a phenotype of naive B cells is progressively replaced by antigen-experienced, antibody-secreting, class-switched plasma cells confined within the perivascular space (PVS). Plasma cells start to appear in the PVS a few months after birth at a time that is consistent with early exposure to common endemic viruses and vaccination antigens. We propose that this latter subset results from previous immunization and constitute an important pool of memory B cells and plasma cells. The maturing thymus would therefore represent an unrecognized niche for B cell memory alongside the bone marrow. We also hypothesize that thymic resident plasma cells significantly contribute to the humoral immunity through their constitutive antibody-secreting capacity. Our proposed studies will use a large collection of human specimens obtained from donors aged 0-2 years to further characterize this niche during its early development. Using mice immunized with model antigens, we will then investigate mechanisms whereby PC accumulate in the thymus and contribute to the overall serum immunity. Aim 1. To characterize the thymic plasma cell niche in the human infant thymus. We will examine the kinetics of development of the thymic PC niche in ~250 human thymus specimens from donors aged 0-2 years. Using immunochemistry, multicolor flow cytometry, gene expression profiling and next generation sequencing- based IGVH repertoire analysis, we will characterize the architecture, molecular signature and clonal composition of thymic PC in human infants. A comparison with PC subsets in the spleen and bone marrow of the same donors will reveal whether thymic PC have unique features. Aim 2. To determine the reactivity profile of thymic plasma cells in human infants. In aim 2, we will assess the frequency of thymic PC reactive to a broad range of antigens towards which human infants are exposed. These include vaccination viral and bacterial antigens, common food antigens as well as ABO blood group antigens. The possible correlation between antigen-specific B cells in the thymus and the presence of serum IgG specific to the same antigens will be examined. Aim 3. To verify the origin of thymic PC and evaluate their role in serological immunity. Mice immunized with model T cell-dependent and T cell-independent antigens, will be used to verified that thymic PC originate from peripheral immune responses. We will then use a series of genetically-deficient mouse strains to investigate the implication of specific chemokines and chemokine receptors as well as survival factors in the migration and maintenance of thymic PC. Lastly, we will evaluate the capacity of antigen-experienced thymic PC to confer humoral immunity upon adoptive transfer to or transplantation of thymus fragments under the renal capsule of recipient animals.

项目摘要 我们的初步研究揭示了B细胞子集随着人类年龄的函数的动态演变 胸腺。出生时出现并显示幼稚B细胞表型的髓质B细胞的初始组合是 逐渐被抗原经验的抗体分泌，类别切换的等离子体细胞所取代 在血管周空间（PVS）内。浆细胞一次出生后几个月开始出现在PVS中 这与早期暴露于普通流行病毒和疫苗接种抗原一致。我们提出了这一点 后一个子集是由先前的免疫引起的，构成了记忆B细胞的重要池， 浆细胞。因此，成熟的胸腺将代表B细胞记忆的未识别的小众市场 旁边的骨髓。我们还假设胸腺驻留浆细胞显着促进 通过其组成抗体分泌能力的体液免疫。我们提出的研究将使用 从0-2岁的捐助者获得的大量人类标本，以进一步表征这种利基市场 在早期发展期间。然后，使用模型抗原免疫的小鼠，我们将研究机制 因此，PC积聚在百里香中并有助于总体血清免疫。 目的1。表征人类婴儿胸腺中的胸腺浆细胞生态位。我们将检查 大约250个人类胸腺标本的胸腺PC生态位开发动力学，来自0-2岁的供体。 使用免疫化学，多色流式细胞仪，基因表达分析和下一代测序 基于IGVH曲目分析，我们将表征结构，分子特征和克隆 胸腺PC在人类婴儿中的组成。与脾和骨髓中的PC子集进行比较 相同的捐助者将揭示胸腺PC是否具有独特的功能。 目标2。确定人类婴儿胸腺浆细胞的反应性曲线。在AIM 2中，我们将 评估胸腺PC对人类婴儿的广泛抗原的反应频率 裸露。其中包括疫苗接种病毒和细菌抗原，常见的食物抗原以及ABO血液 组抗原。胸腺中抗原特异性B细胞与存在的可能相关性 将检查针对同一抗原的血清IgG。 目标3。验证胸腺PC的起源并评估其在血清学免疫中的作用。小鼠免疫 用T细胞依赖性和T细胞独立抗原的模型，将用于验证胸前PC的起源 来自外周免疫反应。然后，我们将使用一系列遗传缺陷的小鼠菌株 研究特定趋化因子和趋化因子受体以及生存因子的影响 胸前PC的迁移和维护。最后，我们将评估抗原经验的百里香的能力 PC在收养转移或移植胸腺碎片时赋予体液免疫力 受体动物的肾囊。