The Regulatory Control Mechanisms of Cross-presentation by Toll-like Receptors

Toll样受体交叉递呈的调控机制

• 批准号: 7432259
• 负责人: Julie Magarian Blander
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7432259
• 关键词: Abnormal Cell; Acute; Address; Antigen Presentation Pathway; Antigens; Apoptotic; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Cell Differentiation process; Cell model; Cells; Class; Complex; Cross Presentation; Cytotoxic T-Lymphocytes; Dendritic Cells; Discrimination; Event; Goals; Heart; Histocompatibility Antigens Class II; Immune system; Immunity; Individual; Kinetics; Knowledge; Ligands; Lysosomes; Major Histocompatibility Complex; Molecular; Molecular Structure; Monitor; Mus; Nature; Organelles; Outcome; Pathway interactions; Peptides; Phagocytosis; Phagolysosome; Phagosomes; Process; Proteins; Rate; Receptor Signaling; Regulation; Signal Pathway; Signal Transduction; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissue Sample; Tissues; Toll-like receptors; Viral; antigen processing; base; design; invariant chain; microbial; pathogen; response

Dendritic cells (DCs) orchestrate either tolerance or immunity. At the heart of this important function lies phagocytosis, which allows DCs to sample the tissue microenvironment and deliver its constituents into endocytic compartments in a process called phagosome maturation. Two important outcomes of phagosome maturation are major histocompatibility complex (MHC) class II presentation and cross-presentation, both of which have important consequences on the activation of CD4 and CD8 T cells, respectively. Crosspresentation allows DCs to acquire antigen from infected or abnormal cells and safely orchestrate MHC class l-restricted responses. During phagocytosis, DCs establish self/non-self discrimination based on the differential engagement of Toll-like receptor (TLR) signaling pathways. We have shown that TLRs control phagosome maturation and one of its consequences, MHC class II presentation. Our current proposal is focused on addressing whether cross-presentation, which relies on the same internalization pathways necessary for MHC class II presentation, is also subject to regulatory control. Our main hypothesis is that cross-presentation is positively regulated by signals from TLRs at multiple levels. We base this hypothesis on our observations that i) phagosome maturation into processing endocytic compartments is induced by TLR signals, ii) MHC class II presentation is controlled by TLRs, and iii) phagosomes are autonomous organelles that individually regulate MHC class II presentation depending on the nature and origin of their cargo. Our long-term goal is to identify regulatory checkpoints that govern antigen presentation pathways within DCs, allowing cellular discrimination between self and non-self. Our specific aims are to: 1. Define the molecular regulation of cross-presentation by signals from TLRs. We will investigate whether TLRs control formation of peptide-MHC class I complexes from phagocytosed cargo, and whether this control is compartmentally restricted within DCs to phagosomes that contain TLR ligands. 2. Define the consequences of TLR control of MHC class II presentation on cross-presentation. We will determine whether TLRs control CDS T cell responses to cellular antigens by determining the availability of CD4 T cell help. This help is necessary for the proper activation and differentiation of CDS T cells. The immune system is tolerant to the body's own cells and tissues. This proposal aims to understand how signals that initiate immunity maintain the existing tolerance to self. The new knowledge we gain will further the design of therapeutic anti-viral and anti-tumor vaccines, and broaden our understanding of autoimmunity

树突状细胞（DCS）协调耐受性或免疫力。这个重要功能的核心在于 吞噬作用，允许DC采样组织微环境并将其成分输送到 在称为吞噬体成熟的过程中，内吞区室。吞噬体的两个重要结果 成熟是主要的组织相容性复合物（MHC）II类表现和交叉表现，这两个 这分别对CD4和CD8 T细胞的激活产生重要影响。交叉代理 允许DC从感染或异常细胞中获取抗原并安全地编排MHC L类限制反应。在吞噬作用期间，DC基于 收费受体（TLR）信号通路的差异参与。我们已经表明TLR控制 吞噬体成熟及其后果之一，MHC II类表现。我们目前的建议是 专注于解决相同内部化途径的交叉表现是否是否 MHC II类表现所需的也需要监管控制。我们的主要假设是 交叉呈阳性受TLR的信号在多个级别上的信号进行了积极调节。我们以此为基础 关于我们观察到的假设，即i）吞噬体成熟到加工内吞室是 由TLR信号诱导的II）II）MHC II类表现由TLR控制，III）吞噬体是 根据性质和 他们的货物的起源。我们的长期目标是确定控制抗原呈递的监管检查点 DC内的途径，允许在自我和非自我之间进行细胞歧视。我们的具体目的是： 1。定义来自TLR的信号对交叉呈递的分子调节。我们将调查 TLR是否控制吞噬货物的肽MHC I类配合物的形成，以及是否是否 该控制在DC中被限制为包含TLR配体的吞噬体。 2。定义了MHC II类介绍对交叉呈现的TLR控制的后果。我们 将确定TLR是否通过确定可用性来控制CDS T细胞对细胞抗原的反应 CD4 T细胞的帮助。这种帮助对于CDS T细胞的适当激活和分化是必要的。 免疫系统对人体自身的细胞和组织具有耐受性。该建议旨在了解如何 启动免疫力的信号保持了对自我的现有宽容。我们获得的新知识将进一步 治疗性抗病毒和抗肿瘤疫苗的设计，并扩大我们对自身免疫性的理解