Lymphatic endothelial cells as inducers of systemic peripheral tolerance
淋巴内皮细胞作为全身外周耐受的诱导剂
基本信息
- 批准号:8775196
- 负责人:
- 金额:$ 19.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-12-01 至 2016-11-30
- 项目状态:已结题
- 来源:
- 关键词:AntigensAutoimmune DiseasesAutoimmune ProcessAutoimmunityCD8B1 geneCellsDendritic CellsDevelopmentEpitopesGene ExpressionGenetic TranscriptionGoalsHealthHumanLeadLymphaticLymphatic Endothelial CellsLymphatic vesselLymphoid TissueMalignant NeoplasmsMediatingMediator of activation proteinMessenger RNAModelingMolecularMonophenol MonooxygenasePeripheralPhenotypePlayPopulationProcessPropertyProteinsRegulatory ElementReticular CellRoleSelf ToleranceSinusStagingStromal CellsStructure of retinal pigment epitheliumT-LymphocyteThymic epithelial cellThymus GlandTissuesWorkbasecentral tolerancelymph nodesmelanocyteperipheral tolerancepreventresponsetraffickingtranscription factor
项目摘要
DESCRIPTION (provided by applicant): The goal of this application is to identify the molecular and cellular mechanisms that control the ability of lymph node resident lymphatic endothelial cells to induce peripheral immunological tolerance. We and two other groups have described a mechanism in which stromal cells in lymph nodes directly express proteins that are normally associated with other tissues. Direct presentation of epitopes derived from these proteins to CD8 T cells leads to abortive proliferation and deletion. Populations of lymph node stromal cells that have been shown to mediate this process include: extra thymic Aire-expressing cells (eTAC), fibroblastic reticular cells, and lymphatic endothelial cells. In particular, we have shown
that CD8 T cell tolerance to an epitope derived from tyrosinase, a protein whose expression is normally confined to melanocytes and retinal pigment epithelial cells, is mediated by lymph node resident lymphatic endothelial cells that adventitiously express it. The 3 lymph node stromal populations defined above express at least partially distinct subsets of peripheral tissue antigens. Peripheral tissue antigens are also expressed in the thymus under the influence of the autoimmune regulatory element Aire. Aire also controls the expression of peripheral tissue antigens in the eTAC lymph node stromal subset. However, neither fibroblastic reticular cells nor lymphatic endothelial cells express Aire, and the mechanisms that control transcription of peripheral tissue antigen mRNAs in these lymph node stromal populations are unknown. One goal of this application is to identify transcription factors that lead to peripheral tissue antige expression in lymphatic endothelial cells. This will illuminate new mechanisms for control of peripheral tissue antigen expression, apart from Aire, that underlie the development of systemic peripheral tolerance. Our preliminary work has established that the lymph node resident lymphatic endothelial cells differ from their counterparts that form tissue lymphatic vessels by elevated expression of peripheral tissue antigens and the ability to present tyrosinase epitopes to tyrosinase-specific T cells. Lymph node resident lymphatic endothelial cells also express a number of immunologically relevant molecules that are not expressed by their tissue lymphatic counterparts. Of these, the most important is PD-L1, which we have shown to be responsible for T cell deletion during tolerance induction. We have also established the existence of subpopulations of lymphatic endothelial cells in the lymph node itself, and shown that tolerance to tyrosinase is primarily induced by those that form the medullary sinus. Thus, the ability of lymphatic endothelial cells to induce peripheral tolerance is regulated by the LN microenvironment. A second major goal of this application is to identify the cellular and molecular aspects of the LN microenvironment that regulate this tolerogenic phenotype. This work will set the stage for further understanding of the role lymphatic endothelial cells may play in self-tolerance and the development of autoimmune disease in humans.
描述(申请人提供):本申请的目标是确定控制淋巴结内皮细胞诱导外周免疫耐受能力的分子和细胞机制。我们和另外两个小组描述了一种机制,在这种机制中,淋巴结中的间质细胞直接表达通常与其他组织相关的蛋白质。将这些蛋白的表位直接提呈给CD8T细胞会导致流产的增殖和缺失。已被证明参与这一过程的淋巴基质细胞包括:胸腺外Aire表达细胞(ETAC)、成纤维细胞网状细胞和淋巴管内皮细胞。特别是,我们已经展示了
CD8T细胞对酪氨酸酶产生的表位的耐受性,通常仅限于黑素细胞和视网膜色素上皮细胞表达,是由淋巴结内皮细胞意外表达酪氨酸酶介导的。上面定义的3个淋巴结间质群体表达至少部分不同的外周组织抗原亚群。在自身免疫调节元件Aire的影响下,外周组织抗原也在胸腺中表达。AIRE还控制eTAC淋巴结间质亚群中外周组织抗原的表达。然而,成纤维细胞网状细胞和淋巴管内皮细胞都不表达Aire,而且这些淋巴结基质细胞中控制外周组织抗原mRNAs转录的机制尚不清楚。这项应用的一个目标是确定导致淋巴管内皮细胞外周组织抗原表达的转录因子。这将阐明控制外周组织抗原表达的新机制,而不是AIRE,这是全身外周耐受发展的基础。我们的初步工作证实,淋巴内皮细胞不同于形成组织淋巴管的淋巴管内皮细胞,其原因是外周组织抗原表达增加,并有能力将酪氨酸酶表位呈递给酪氨酸酶特异性T细胞。淋巴结内皮细胞也表达许多免疫相关分子,而它们的组织淋巴管内皮细胞则不表达。其中,最重要的是PD-L1,我们已经证明它在耐受诱导过程中负责T细胞的缺失。我们还证实了淋巴管内皮细胞亚群在淋巴结中的存在,并表明对酪氨酸酶的耐受主要是由形成髓窦的细胞诱导的。因此,淋巴管内皮细胞诱导外周耐受的能力受LN微环境的调节。这项应用的第二个主要目标是确定调节这种耐受表型的LN微环境的细胞和分子方面。这项工作将为进一步了解淋巴管内皮细胞在人类自身耐受和自身免疫性疾病发展中可能发挥的作用奠定基础。
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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VICTOR H ENGELHARD其他文献
VICTOR H ENGELHARD的其他文献
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{{ truncateString('VICTOR H ENGELHARD', 18)}}的其他基金
Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors
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10194416 - 财政年份:2019
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Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors
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10401362 - 财政年份:2019
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Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors
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9926230 - 财政年份:2019
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10524125 - 财政年份:2019
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Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors
操纵微环境和脉管系统以增强 T 细胞浸润肿瘤
- 批准号:
10625302 - 财政年份:2019
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$ 19.32万 - 项目类别:
Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors
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Lymph node-like vasculature and naive T cell infiltration into tumors
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8813956 - 财政年份:2015
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Fluorescence molecular tomography to study T cell infiltration into tumors
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8902076 - 财政年份:2014
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Immunity to MHC-restricted phosphopeptides in healthy donors and cancer patients
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8800677 - 财政年份:2014
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$ 19.32万 - 项目类别:
Immunity to MHC-restricted phosphopeptides in healthy donors and cancer patients
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8930114 - 财政年份:2014
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