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

建议书摘要 树突状细胞(DC)协调耐受或免疫。这一重要功能的核心是 吞噬作用，允许DC对组织微环境进行采样，并将其成分输送到 吞噬小体成熟过程中的胞内隔间。吞噬小体的两个重要结果 成熟是主要组织相容性复合体(MHC)II类呈现和交叉呈现，两者都是 它们分别对CD_4和CD_8 T细胞的激活有重要影响。克罗斯- 递呈允许DC从受感染或异常的细胞中获得抗原，并安全地协调MHC I类- 受限的反应。在吞噬过程中，DC根据差异建立自我/非自我区分 Toll样受体(TLR)信号通路的参与。我们已经证明了TLRs控制着吞噬小体 成熟及其后果之一，MHC II类呈现。我们目前的提案主要集中在 解决交叉呈现是否依赖于MHC所需的相同内化途径 第二类陈述，也受监管。我们的主要假设是交叉陈述是 受到来自多个水平的TLRs信号的正向调节。我们把这一假设建立在观察的基础上。 即i)吞噬小体成熟为加工内细胞室是由TLR信号诱导的，ii)MHC II类递呈受TLRs控制，III)吞噬小体是独立的独立细胞器 根据货物的性质和来源对MHC II类呈报进行监管。我们的长期目标是 识别管理DC内抗原递送途径的监管检查点，允许细胞 自我与非我的区别。我们的具体目标是： 1.确定TLRs信号对交叉呈现的分子调控。我们会调查的 TLRs是否控制吞噬的货物形成多肽-MHC-I类复合体，以及这是否 在DC中，控制被分隔地限制在含有TLR配体的吞噬小体上。 2.定义MHC II类呈现的TLR控制对交叉呈现的影响。我们会 确定TLRs是否影响CD8T细胞对细胞抗原的应答 CD4T细胞有帮助。这种帮助对于CD8T细胞的正确激活和分化是必要的。建议书叙事 免疫系统对人体自身的细胞和组织具有耐受性。这项提案旨在了解如何 启动对微生物病原体免疫的信号维持对自身现有的耐受性。新知识 我们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 自身免疫力的问题。

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.