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: 8278660
• 负责人: Julie Magarian Blander
• 金额: $ 41.53万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278660
• 关键词: Abnormal Cell; Acute; Address; Antigen Presentation Pathway; Antigens; Apoptotic; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Cell model; Cells; 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; Receptor Signaling; Regulation; Signal Pathway; Signal Transduction; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissue Sample; Tissues; Toll-like receptors; Viral; antigen processing; base; design; invariant chain; microbial; pathogen; response

PROPOSAL SUMMARY 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. Cross- presentation allows DCs to acquire antigen from infected or abnormal cells and safely orchestrate MHC class I- 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 influence CD8 T cell responses to cellular antigens by controlling the availability of CD4 T cell help. This help is necessary for the proper activation and differentiation of CD8 T cells. PROPOSAL NARRATIVE The immune system is tolerant to the body's own cells and tissues. This proposal aims to understand how signals that initiate immunity to microbial pathogens 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.

提案摘要 树突状细胞（DC）协调耐受或免疫。这一重要功能的核心在于 吞噬作用，其允许DC对组织微环境进行采样并将其成分递送到 吞噬体成熟过程中的内吞区室。吞噬体的两个重要成果 成熟是主要组织相容性复合体（MHC）II类呈递和交叉呈递，两者都是 其分别对CD 4和CD 8 T细胞的活化具有重要影响。交叉- 呈递允许DC从感染或异常细胞获得抗原，并安全地协调I类MHC。 有限的回应。在吞噬过程中，DCs根据不同的细胞因子建立自身/非自身的区分。 Toll样受体（TLR）信号通路的参与。我们已经证明TLR控制吞噬体 成熟及其后果之一，MHC II类呈递。我们目前的建议集中在 解决交叉呈递是否依赖于MHC所必需的相同内化途径， 第二类介绍，也受到监管控制。我们的主要假设是交叉呈现是 在多个水平上受到TLR信号的正调控。我们根据我们的观察得出这个假设 i）吞噬体成熟为加工内吞区室是由TLR信号诱导的，ii）MHC II类呈递由TLR控制，和iii）吞噬体是独立的细胞器， 调节MHC II类呈递取决于其货物的性质和来源。我们的长期目标是 鉴定控制DC内抗原呈递途径的调节检查点， 自我与非自我的区别。我们的具体目标是： 1.定义TLR信号对交叉呈递的分子调控。我们将调查 TLR是否控制吞噬货物的肽-MHC I类复合物的形成，以及这是否 对照在DC内被区室性地限制于含有TLR配体的吞噬体。 2.定义TLR控制MHC II类呈递对交叉呈递的影响。我们将 通过控制TLR的可用性来确定TLR是否影响CD 8 T细胞对细胞抗原的应答， CD 4 T细胞帮助。这种帮助对于CD 8 T细胞的适当活化和分化是必要的。提案说明 免疫系统对人体自身的细胞和组织具有耐受性。该提案旨在了解如何 启动对微生物病原体的免疫的信号维持对自身的现有耐受性。新知识 我们的收获将进一步设计治疗性抗病毒和抗肿瘤疫苗，并拓宽我们的理解 自身免疫性