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:10229524
- 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 AnimalDevelopmentDiseaseEpithelialEpithelial CellsExposure toFOXP3 geneGenerationsGenetic DeterminismHomeostasisHumanImmune responseImmune systemImmunoglobulin AImmunologicsImpairmentInflammationInstructionIntestinesKnock-outKnockout MiceLifeLinkLiverMediatingMucous MembraneMusNeonatalNewborn InfantOrganOutputParentsPerinatalPerinatal ExposurePeripheralPeyer&aposs PatchesPlayPregnancyProcessProductionRegulatory T-LymphocyteRoleSiteSmall IntestinesSpleenStructure of thymic medullaSurfaceSystemic diseaseT-Cell ActivationT-LymphocyteTestingThymic epithelial cellThymus GlandTissuesautoreactive T cellcentral tolerancedysbiosiseffector T cellgut microbiotaimprovedinflammatory disease of the intestineknockout animalmicrobial colonizationmicrobial communitymicrobial compositionmicrobiotamouse modelmucosal microbiotaneonatenormal microbiotanovel strategiesperipheral tolerancepupthymocyte
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细胞耐受自身的指令发生在胸腺中,通过胸腺细胞的相互作用
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)
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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:
10020918 - 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
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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
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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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$ 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:
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