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

• 批准号: 8622327
• 负责人: VICTOR H ENGELHARD
• 金额: $ 23.27万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8622327
• 关键词: Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD8B1 gene; Cells; Dendritic Cells; Development; Epitopes; Gene Expression; Genetic Transcription; Goals; Human; Lead; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Lymphoid Tissue; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Monophenol Monooxygenase; Peripheral; Phenotype; Play; Population; Process; Property; Proteins; Regulatory Element; Reticular Cell; Role; Self Tolerance; Sinus; Staging; Stromal Cells; Structure of retinal pigment epithelium; T-Lymphocyte; Thymic epithelial cell; Thymus Gland; Tissues; Work; base; central tolerance; lymph nodes; melanocyte; peripheral tolerance; prevent; public health relevance; response; trafficking; transcription factor

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（由申请人提供）：本申请的目的是确定控制淋巴结常驻淋巴内皮细胞能力诱导周围免疫耐受性的分子和细胞机制。我们和其他两个组描述了一种机制，其中淋巴结中的基质细胞直接表达通常与其他组织相关的蛋白质。从这些蛋白质到CD8 T细胞的表位直接表现会导致流产性增殖和缺失。已证明可以介导此过程的淋巴结基质细胞的群体包括：表达胸腺AIRE的额外表达细胞（ETAC），成纤维细胞网状细胞和淋巴内皮细胞。特别是，我们已经表明 CD8 T细胞对源自酪氨酸酶的表位的耐受性，酪氨酸酶的表达通常局限于黑素细胞和视网膜色素上皮细胞，是由淋巴结势淋巴淋巴内皮细胞介导的。上面定义的3个淋巴结基质种群至少表达了周围组织抗原的至少部分不同的子集。在自身免疫调节元件AIRE的影响下，在胸腺中也表达外周组织抗原。 AIRE还控制ETAC淋巴结基群中周围组织抗原的表达。但是，成纤维细胞网状细胞和淋巴内皮细胞都不表达AIRE，以及控制这些淋巴结基质群体外周组织抗原mRNA的转录的机制尚不清楚。该应用的一个目标是鉴定导致淋巴内皮细胞周围组织抗体表达的转录因子。这将阐明除Aire外，以控制全身外围耐受性的基础的新机制，以控制周围组织抗原表达。我们的初步工作已经确定，淋巴结驻留的淋巴内皮细胞与它们的淋巴管抗原的表达升高以及对酪氨酸酶特异性T细胞的阳性酶表现效果的能力升高，与它们的淋巴管血管形成组织淋巴管。淋巴结势淋巴的内皮细胞还表达了许多与组织淋巴相当的免疫学相关分子。其中，最重要的是PD-L1，我们已证明在耐受性诱导过程中是T细胞缺失的原因。我们还确定了淋巴结淋巴结本身中淋巴内皮细胞的亚群的存在，并表明对酪氨酸酶的耐受性主要是由形成髓窦的耐受性诱导的。因此，LN微环境调节了淋巴内皮细胞诱导周围耐受性的能力。该应用的第二个主要目标是确定调节这种耐受性表型的LN微环境的细胞和分子方面。这项工作将为进一步理解淋巴内皮细胞的作用奠定阶段，这可能在人类自我耐受性和自身免疫性疾病的发展中起着作用。