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）协调耐受或免疫。这一重要功能的核心是吞噬作用，它允许dc在组织微环境中取样，并在一个称为吞噬体成熟的过程中将其成分输送到内吞室。吞噬体成熟的两个重要结果是主要组织相容性复合体（MHC） II类呈递和交叉呈递，两者分别对CD4和CD8 T细胞的激活产生重要影响。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类限制性反应。在吞噬过程中，dc基于toll样受体（TLR）信号通路的不同参与建立了自我/非自我区分。我们已经证明tlr控制吞噬体成熟及其后果之一，MHC II类呈现。我们目前的建议侧重于解决交叉呈递是否也受到监管控制，交叉呈递依赖于MHC II类呈递所必需的相同内化途径。我们的主要假设是交叉呈现在多个水平上受到tlr信号的积极调节。我们的这一假设基于我们的观察：1)吞噬体成熟到加工内吞室是由TLR信号诱导的，2)MHC ii类呈递由TLR控制，3)吞噬体是自主的细胞器，根据其货物的性质和来源单独调节MHC ii类呈递，4)我们的新结果表明，在缺乏TLR信号的情况下，交叉呈递受到损害。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，允许细胞区分自我和非自我。我们的具体目标是：1。确定TLR信号是否调节交叉呈现。我们将研究TLRs是否控制吞噬货物中肽- mhc I类复合物的形成，从而控制CD8 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在dc内被区隔限制为含有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。我们将通过确定CD4 T细胞帮助的可用性来确定TLRs是否控制CD8 T细胞对细胞抗原的反应。这种帮助对于CD8 T细胞的正常激活和分化是必要的。

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.