Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice

新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受

基本信息

项目摘要

SUMMARY. Instruction of T cells to be tolerant to self occurs in the thymus through interactions of thymocytes with the epithelial cell compartment. While the thymus serves as the primary site of immunologic T cell tolerance to self-antigens and production of thymic T regulatory (tTreg) cells, microbial communities in the gut also regulate the function of T effector (Teff) cells and production of peripheral Treg cells (pTreg). Microbial colonization of mucosal tissues in early life facilitates tolerance to commensal and environmental antigens. Abnormal colonization during this period can have long-term consequences contributing to development of mucosal and systemic disease later in life. The mechanisms that regulate perinatal immune- system-microbiota interactions to achieve long-term homeostasis are poorly defined. We previously generated mice (Traf6ΔTEC) whose thymus was devoid of medullary thymic epithelial cell (mTECs). mTEC depletion had a two-faceted effect on the T cell output: generation of autoreactive T cells and a 50% reduction in the numbers of tTregs. The reduction in tTregs in Traf6ΔTEC mice in turn associated with: 1) reduced numbers of Foxp3+ Tregs and T follicular (Tf) cells in the Peyer’s Patches (PP) of the small intestine and small intestinal inflammation; 2) skewed production of IgA-coated bacteria; and 3) altered microbial composition in the gut of knockout animals. Together, these results suggest that the aberrant T cell compartment generated in the thymus of Traf6ΔTEC mice and associated changes in the microbiota may adversely impact survival of newborn Traf6ΔTEC mice. In this proposal we will use the Traf6ΔTEC mouse model to better understand how T cells and the gut microbiota influence each other to establish perinatal organ-specific tolerance. We will test the following hypothesis: Impaired tTreg cell selection in Traf6ΔTEC mice, induces changes in their gut microbiota that cannot support induction of perinatal tolerance and viable progeny. Perinatal exposure of knockout pups to normal microbiota is required for tolerance induction and survival. To test this hypothesis we will: 1) examine whether exposure to normal microbiota is sufficient for promoting survival of newborn Traf6ΔTEC mice and identify microbial communities from WT mice that rescue Traf6ΔTEC neonate survival; 2) examine whether induction of neonatal tolerance is compromised in newborn Traf6ΔTEC mice that are not exposed to normal microbiota; and 3) examine if the altered T cell compartment of Traf6ΔTEC mice acts as a genetic determinant of intestinal dysbiosis and neonatal lethality. Defining early-life tolerance mechanisms could have a profound impact on our understanding of human autoimmune disease development and may help us devise novel strategies for managing and/or treating T cell mediated autoimmune diseases.
总结。T细胞通过胸腺细胞的相互作用指示T细胞对自身的耐受 与上皮细胞隔间。而胸腺是免疫T细胞的主要部位 对自身抗原的耐受性和胸腺T调节细胞(TTreg)的产生,微生物群落 肠道还调节T效应细胞的功能和外周Treg细胞(PTreg)的产生。 早期生命中粘膜组织的微生物定植促进了对共生和环境的耐受性 抗原。在此期间的不正常殖民可能会产生长期后果 在以后的生活中发展成粘膜和全身疾病。调节围产期免疫的机制- 实现长期动态平衡的系统-微生物群相互作用还没有明确的定义。我们之前 产生的小鼠(TRAF6、Δ、TEC)胸腺无髓质上皮细胞(MTECs)。MTEC 耗竭对T细胞的输出有两方面的影响:产生自身反应性T细胞和减少50% 在tTregs的数量上。TRAF6Δ受精小鼠tTregs的减少依次与:1)减少 Foxp3+Tregs和T滤泡(Tf)细胞在小肠Peyer‘s patches(PP)和 小肠炎;2)包被IgA的细菌产生扭曲;3)微生物改变 基因敲除动物肠道中的成分。综上所述,这些结果表明,异常T细胞 TRAF6-Δ-TEC小鼠胸腺产生的小室及其相关微生物区系的变化 可能会对新生的TRAF6ΔTEC小鼠的存活率产生不利影响。在本建议书中,我们将使用Traf6ΔTEC 建立小鼠模型以更好地了解T细胞和肠道微生物区系如何相互影响 围产期器官特异性耐受性。我们将检验以下假设:受损的tTreg细胞选择 TRAF6TEC小鼠,诱导其肠道微生物区系的变化,而不支持围产期耐受的诱导 以及可存活的后代。围产期基因敲除幼鼠暴露在正常微生物群中是耐受所必需的 诱导和生存。为了验证这一假设,我们将:1)检查暴露在正常微生物群中是否 足以促进新生TRAF6Δ小鼠存活并从WT中鉴定微生物群落 挽救Traf6ΔTEC新生儿存活的小鼠;2)检查是否诱导新生儿耐受 在未暴露于正常微生物区系的新生TRAF6ΔTEC小鼠中受到损害;以及3)检查 TRAF6ΔTEC小鼠T细胞亚群改变是肠道菌群失调的遗传决定因素 新生儿死亡率。定义早期生活耐受机制可能会对我们的 了解人类自身免疫性疾病的发展,并可能帮助我们设计新的策略 管理和/或治疗T细胞介导的自身免疫性疾病。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

KONSTANTINA ALEXANDROPOULOS其他文献

KONSTANTINA ALEXANDROPOULOS的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('KONSTANTINA ALEXANDROPOULOS', 18)}}的其他基金

Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice
新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受
  • 批准号:
    10463592
  • 财政年份:
    2019
  • 资助金额:
    $ 46.23万
  • 项目类别:
Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice
新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受
  • 批准号:
    10229524
  • 财政年份:
    2019
  • 资助金额:
    $ 46.23万
  • 项目类别:
Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice
新生和成年自身免疫小鼠中微生物群介导的 T 细胞耐受
  • 批准号:
    10684667
  • 财政年份:
    2019
  • 资助金额:
    $ 46.23万
  • 项目类别:
Mechanism of autoimmune hepatitis development in a novel mouse model
新型小鼠模型中自身免疫性肝炎发生的机制
  • 批准号:
    9516717
  • 财政年份:
    2016
  • 资助金额:
    $ 46.23万
  • 项目类别:
Role of the thymic epithelium on the outcome of allogeneic transplantation
胸腺上皮对同种异体移植结果的作用
  • 批准号:
    8308335
  • 财政年份:
    2011
  • 资助金额:
    $ 46.23万
  • 项目类别:
Role of the thymic epithelium on the outcome of allogeneic transplantation
胸腺上皮对同种异体移植结果的作用
  • 批准号:
    8107902
  • 财政年份:
    2011
  • 资助金额:
    $ 46.23万
  • 项目类别:
Role of the thymic epithelium on the outcome of allogeneic transplantation
胸腺上皮对同种异体移植结果的作用
  • 批准号:
    8501268
  • 财政年份:
    2011
  • 资助金额:
    $ 46.23万
  • 项目类别:
Role of Chat-H in chemokine-induced T lymphocyte migration and trafficking
Chat-H 在趋化因子诱导的 T 淋巴细胞迁移和运输中的作用
  • 批准号:
    7317277
  • 财政年份:
    2007
  • 资助金额:
    $ 46.23万
  • 项目类别:
Role of Chat-H in chemokine-induced T lymphocyte migration and trafficking
Chat-H 在趋化因子诱导的 T 淋巴细胞迁移和运输中的作用
  • 批准号:
    7802902
  • 财政年份:
    2007
  • 资助金额:
    $ 46.23万
  • 项目类别:
Role of Chat-H in chemokine-induced T lymphocyte migration and trafficking
Chat-H 在趋化因子诱导的 T 淋巴细胞迁移和运输中的作用
  • 批准号:
    8076331
  • 财政年份:
    2007
  • 资助金额:
    $ 46.23万
  • 项目类别:

相似国自然基金

Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
    2022J011295
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
  • 批准号:
    30801055
  • 批准年份:
    2008
  • 资助金额:
    19.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Bovine herpesvirus 4 as a vaccine platform for African swine fever virus antigens in pigs
牛疱疹病毒 4 作为猪非洲猪瘟病毒抗原的疫苗平台
  • 批准号:
    BB/Y006224/1
  • 财政年份:
    2024
  • 资助金额:
    $ 46.23万
  • 项目类别:
    Research Grant
Uncovering tumor specific antigens and vulnerabilities in ETP-acute lymphoblastic leukemia
揭示 ETP-急性淋巴细胞白血病的肿瘤特异性抗原和脆弱性
  • 批准号:
    480030
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
    Operating Grants
A novel vaccine approach combining mosquito salivary antigens and viral antigens to protect against Zika, chikungunya and other arboviral infections.
一种结合蚊子唾液抗原和病毒抗原的新型疫苗方法,可预防寨卡病毒、基孔肯雅热和其他虫媒病毒感染。
  • 批准号:
    10083718
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
    Small Business Research Initiative
Regulation of B cell responses to vaccines by long-term retention of antigens in germinal centres
通过在生发中心长期保留抗原来调节 B 细胞对疫苗的反应
  • 批准号:
    MR/X009254/1
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
    Research Grant
Adaptive Discrimination of Risk of Antigens in Immune Memory Dynamics
免疫记忆动态中抗原风险的适应性辨别
  • 批准号:
    22KJ1758
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
22-ICRAD Call 2 - Improving the diagnosis of tuberculosis in domestic ruminants through the use of new antigens and test platforms
22-ICRAD 呼吁 2 - 通过使用新抗原和测试平台改善家养反刍动物结核病的诊断
  • 批准号:
    BB/Y000927/1
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
    Research Grant
Protective immunity elicited by distinct polysaccharide antigens of classical and hypervirulent Klebsiella
经典和高毒力克雷伯氏菌的不同多糖抗原引发的保护性免疫
  • 批准号:
    10795212
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
Integrative proteome analysis to harness humoral immune response against tumor antigens
综合蛋白质组分析利用针对肿瘤抗原的体液免疫反应
  • 批准号:
    23K18249
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens
功能独特的人类 CD4 T 细胞对新型进化选择的结核分枝杆菌抗原的反应
  • 批准号:
    10735075
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
Targeting T3SA proteins as protective antigens against Yersinia
将 T3SA 蛋白作为针对耶尔森氏菌的保护性抗原
  • 批准号:
    10645989
  • 财政年份:
    2023
  • 资助金额:
    $ 46.23万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了