Control of lymphocyte homeostasis by iCD8a cells and osteopontin
Control of lymphocyte homeostasis by iCD8a cells and osteopontin
批准号:
9381773
负责人:
Danyvid Olivares-Villagomez
金额:
$35.55万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-07-05 至 2022-06-30
关键词:
Adoptive TransferAlpha CellAntibodiesAreaBiologicalBiologyCD8-Positive T-LymphocytesCD8B1 geneCellsCitrobacter rodentiumDataDevelopmentDiseaseDisease modelEnhancersEnvironmentEpithelialFoundationsGene Expression ProfileGrantHealthHomeostasisHumanImmuneImmune responseImmunodeficient MouseImmunologicsInfectionInflammationInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInflammatory disease of the intestineInterleukin-12Intestinal DiseasesIntestinesKnowledgeLigandsLymphocyteLymphocyte BiologyLymphocyte SubsetLymphoidLymphoid CellMaintenanceModelingMouse StrainsMucosal Immune ResponsesMusOsteogenesisPathogenicityPhenotypePopulationPreventiveProcessProductionPublicationsReceptors, Antigen, B-CellResearch ProposalsRoleSourceStimulusSymbiosisT-LymphocyteTNFRSF5 geneTherapeuticTissuesWild Type Mousechemokinecytokineintestinal epitheliumintraepithelialmicroorganismnovelosteopontinprophylactictissue regeneration
中文摘要
总结
在本申请中,我们提出研究先天性CD 8+细胞(或iCD 8+细胞)的生物学特征,
本研究组发现了存在于肠上皮中的新淋巴样细胞群。这其中的一个标志是
群体的主要特征是表达CD 8受体,缺乏T和B细胞受体,以及产生
细胞因子/趋化因子,其指示先天免疫表型。iCD 8巨噬细胞是
肠上皮中的骨桥蛋白是一种细胞因子,以其在组织重塑中的作用而闻名,
刺激Th 1和Th 17免疫应答的能力。有趣的是,使用缺乏iCD 8的小鼠品系,
细胞(E8 I小鼠; E8 I是IEL中CD 8受体表达的重要增强剂),我们发现,
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与野生型小鼠相比,肠上皮中的骨桥蛋白减少,并且E8 I-/-小鼠
NKp 46 +NK1.1+ IEL缺乏。这些和其他初步结果导致了这样的假设,
iCD 8 β细胞通过产生骨桥蛋白等因子,促进存活,
IEL的维护为了实现这一假设,我们提出了以下补充,但
独立目标:Aim 1.确定iCD 8 β细胞和骨桥蛋白对IEL的贡献
维持和生存。在这个目标中,我们将确定:a)iCD 8 β细胞和骨桥蛋白对骨形成的影响。
不同IEL亚群的存活和增殖; B)iCD 8+细胞和骨桥蛋白在IEL亚群中的影响。
肠的免疫环境;和c)骨桥蛋白配体在IEL稳态中的作用。目标2.到
明确iCD 8巨噬细胞和骨桥蛋白在肠道炎症中的作用。本节我们将
确定iCD 8 β细胞和骨桥蛋白在三种不同疾病模型中的作用:
通过抗CD 40抗体治疗的炎症,B)啮齿类柠檬酸杆菌感染,和c)炎症
由效应T细胞过继转移到免疫缺陷小鼠引起。目标3:确定
通过iCD 8 β细胞控制IEL稳态的机制。我们先前的出版物表明IL-12
为iCD 8 β细胞的活化提供刺激。在本节中,我们将确定a)IL-12在
iCD 8 β细胞的活化,对OPN分泌和IEL存活的影响,和B)我们将确定
IEL对iCD 8+细胞/OPN刺激的响应的基因表达特征。
英文摘要
SUMMARY
In this application we propose to investigate the biological features of innate CD8 cells (or iCD8 cells), a
novel lymphoid population present in the intestinal epithelium discovered by our group. A hallmark of this
population is the expression of CD8, lack of T and B cell receptors, and the production of
cytokines/chemokines that indicate an innate immune phenotype. iCD8 cells are a main source of
osteoponin in the intestinal epithelium, a cytokine known for its role in tissue remodeling but also for its
capacity to stimulate Th1 and Th17 immune responses. Interestingly, using a strain of mice lacking iCD8
cells (E8I mice; E8I is an essential enhancer for CD8 expression in IEL) we found that the levels of
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osteopontin in the intestinal epithelium are decreased in comparison to wild type mice, and that E8I-/- mice
have a deficiency in NKp46+NK1.1+ IEL. These and other preliminary results have led to the hypothesis that
iCD8 cells, through production of factors such as osteopontin, promote the survival and
maintenance of IEL. In order to pursue this hypothesis, we propose the following complementary, yet
independent aims: Aim1. To determine the contribution of iCD8 cells and osteopontin to IEL
maintenance and survival. In this aim we will determine: a) the impact of iCD8 cells and osteopontin in
the survival and proliferation of different IEL subsets; b) the impact of iCD8 cells and osteopontin in the
immune environment of the intestines; and c) the role of osteopontin ligands in IEL homeostasis. Aim 2. To
define the role of iCD8 cells and osteopontin during intestinal inflammation. In this section we will
determine the role of iCD8 cells and osteopontin in three different disease models: a) intestinal
inflammation by anti-CD40 antibody treatment, b) Citrobacter rodentium infection, and c) inflammation
caused by adoptive transfer of effector T cells into immunodeficient mice. Aim 3. To determine the
mechanisms controlling IEL homeostasis by iCD8 cells. Our previous publication indicates that IL-12
provides stimulus for activation of iCD8 cells. In this section we will determine a) the impact of IL-12 in
activation of iCD8 cells, with implications on OPN secretion and IEL survival, and b) we will determine the
gene expression signature of IEL responding to iCD8 cell/OPN stimulation.
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会议论文
Control of lymphocyte homeostasis by iCD8a cells and osteopontin
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批准号:10178005
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项目类别:
-
资助金额:$35.55万
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财政年份:2017
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负责人:Danyvid Olivares-Villagomez
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依托单位:
Characterization of CD8a cells as a novel immune population of the intestines
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批准号:9252837
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项目类别:
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资助金额:$15.83万
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财政年份:2014
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负责人:Danyvid Olivares-Villagomez
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依托单位:
海外基金