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
- 批准号:10684667
- 负责人:
- 金额:$ 46.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-19 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAntigensAutoantigensAutoimmune DiseasesAutoimmunityBacteriaCD4 Positive T LymphocytesCell CompartmentationCellsCessation of lifeColonControl AnimalDevelopmentDiseaseEpithelial CellsEpitheliumExposure toFOXP3 geneGenerationsGenetic DeterminismHeterozygoteHomeostasisHumanImmune responseImmune systemImmunoglobulin AImmunologicsImpairmentInflammationInstructionIntestinesKnock-outKnockout MiceLifeLinkLiverMediatingMucous MembraneMusNeonatalNewborn InfantOrganOutputParentsPerinatalPerinatal ExposurePeripheralPeyer&aposs PatchesPlayPregnancyProcessProductionRegulatory T-LymphocyteRoleSiteSmall IntestinesSpleenStructure of thymic medullaSurfaceSystemic diseaseT-Cell ActivationT-LymphocyteTestingThymic epithelial cellThymus GlandTissuesautoreactive T celldysbiosiseffector T cellgut inflammationgut microbiotaimprovedknockout animalmicrobial colonizationmicrobial communitymicrobial compositionmicrobiotamouse modelmucosal microbiotaneonatenormal microbiotanovel strategiespupthymocyte
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.
概括。胸腺中通过胸腺细胞的相互作用指示 T 细胞耐受自身
与上皮细胞区室。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 (tTreg) 细胞的产生、微生物群落
肠道还调节效应 T (Teff) 细胞的功能和外周 Treg 细胞 (pTreg) 的产生。
生命早期粘膜组织的微生物定植促进了对共生和环境的耐受
抗原。在此期间的异常定植可能会产生长期后果,导致
晚年出现粘膜和全身疾病。调节围产期免疫的机制
实现长期稳态的系统-微生物群相互作用尚不清楚。我们之前
生成的小鼠(Traf6ΔTEC)的胸腺缺乏髓质胸腺上皮细胞(mTEC)。 mTEC
耗竭对 T 细胞输出产生两个方面的影响:自身反应性 T 细胞的产生和减少 50%
tTreg 的数量。 Traf6ΔTEC 小鼠中 tTreg 的减少又与以下因素相关:1)
小肠集合淋巴集结 (PP) 中 Foxp3+ Tregs 和滤泡 T (Tf) 细胞的数量
小肠炎症; 2) IgA 包被细菌的生产存在偏差; 3)改变微生物
基因敲除动物肠道中的成分。总之,这些结果表明异常 T 细胞
Traf6ΔTEC 小鼠胸腺中产生的隔室以及微生物群的相关变化
可能会对新生 Traf6ΔTEC 小鼠的生存产生不利影响。在本提案中,我们将使用 Traf6ΔTEC
小鼠模型,以更好地了解 T 细胞和肠道微生物群如何相互影响,以建立
围产期器官特异性耐受性。我们将检验以下假设: tTreg 细胞选择受损
Traf6ΔTEC 小鼠诱导肠道微生物群发生变化,无法支持诱导围产期耐受性
和可存活的后代。基因敲除幼崽在围产期暴露于正常微生物群是耐受性所必需的
诱导和生存。为了检验这个假设,我们将:1)检查暴露于正常微生物群是否是
足以促进新生 Traf6ΔTEC 小鼠的存活并从 WT 中识别微生物群落
拯救 Traf6ΔTEC 新生儿存活的小鼠; 2) 检查是否诱导新生儿耐受
未接触正常微生物群的新生 Traf6ΔTEC 小鼠受到损害; 3)检查是否
Traf6ΔTEC 小鼠 T 细胞区室的改变是肠道菌群失调的遗传决定因素
新生儿死亡率。定义生命早期的耐受机制可能会对我们产生深远的影响
了解人类自身免疫性疾病的发展,可能有助于我们制定新的策略
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)
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KONSTANTINA ALEXANDROPOULOS其他文献
KONSTANTINA ALEXANDROPOULOS的其他文献
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{{ 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:
10020918 - 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
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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
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$ 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
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8501268 - 财政年份:2011
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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
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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
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$ 46.23万 - 项目类别:
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