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

描述（由申请人提供）：树突状细胞（DC）协调耐受性或免疫性。吞噬作用是这一重要功能的核心，它允许DC对组织微环境进行采样，并在称为吞噬体成熟的过程中将其成分递送到内吞区室中。吞噬体成熟的两个重要结果是主要组织相容性复合物（MHC）II类呈递和交叉呈递，这两者分别对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MHC I类限制性应答。在吞噬过程中，DC基于Toll样受体（TLR）信号通路的差异参与建立自我/非自我辨别。我们已经表明，TLR控制吞噬体成熟及其后果之一，MHC II类呈递。我们目前的建议是集中在解决是否交叉呈递，这依赖于相同的内化途径所需的MHC II类呈递，也受到监管控制。我们的主要假设是，交叉呈递在多个水平上受到TLR信号的正调控。我们基于我们的观察，即i）吞噬体成熟为加工内吞区室是由TLR信号诱导的，ii）MHC II类呈递是由TLR控制的，iii）吞噬体是独立的细胞器，根据其货物的性质和来源单独调节MHC II类呈递，iv）我们的新结果表明，在TLR信号不存在的情况下，交叉呈递受损。我们的长期目标是确定控制DC内抗原呈递途径的调节检查点，从而允许细胞区分自体和非自体。我们的具体目标是：1.确定TLR信号是否调节交叉呈递。我们将研究TLR是否控制吞噬货物的肽-MHC I类复合物的形成，从而控制CD 8 T细胞对来自这些货物的抗原的活化。我们将研究这种控制是否是区室限制在DC内的吞噬体含有TLR配体。2.定义TLR控制MHC II类呈递对交叉呈递的影响。我们将通过确定CD 4 T细胞帮助的可用性来确定TLR是否控制CD 8 T细胞对细胞抗原的应答。这种帮助对于CD 8 T细胞的适当活化和分化是必要的。 免疫系统对人体自身的细胞和组织具有耐受性。该提案旨在了解启动对微生物病原体免疫的信号如何维持对自身的现有耐受性。我们获得的新知识将进一步设计治疗性抗病毒和抗肿瘤疫苗，并拓宽我们对自身免疫的理解。

DESCRIPTION (provided by applicant): 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, iii) phagosomes are autonomous organelles that individually regulate MHC class II presentation depending on the nature and origin of their cargo, and iv) our new results indicate that cross-presentation is impaired in the absence of TLR signals. 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. Determine whether TLR signals regulate cross-presentation. We will investigate whether TLRs control formation of peptide-MHC class I complexes from phagocytosed cargo and thereby CD8 T cell activation to antigens derived from these cargos. We will investigate 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 CD8 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 CD8 T cells. PUBLIC HEALTH RELEVANCE 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.