Non-Canonical Cross-presentation in Dendritic Cells Upon TAP Blockade

TAP 阻断后树突状细胞中的非典型交叉呈递

• 批准号: 9404238
• 负责人: Julie Magarian Blander
• 金额: $ 41.93万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9404238
• 关键词: Alpha Cell; Antigen Presentation; Antigens; Antiviral Agents; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Back; Basic Science; Binding; Biochemical; Biological; Bypass; CD8-Positive T-Lymphocytes; Cathepsins; Cells; Cellular biology; Chronic; Communicable Diseases; Complex; Coupling; Cowpox virus; Cross Presentation; Cytosol; Dendritic Cells; Detection; Disease; Down-Regulation; ERp57; Endoplasmic Reticulum; Endosomes; Genetic; Genetic Polymorphism; Golgi Apparatus; HIV; Heterodimerization; Human; Immune; Impairment; Inflammation; Intervention; Lead; Ligands; Light; Major Histocompatibility Complex; Malaria; Malignant Neoplasms; Mediating; Membrane; Molecular; Mus; Mutation; Pathway interactions; Patients; Pattern recognition receptor; Peptide Hydrolases; Peptides; Phagocytes; Phagosomes; Predisposition; Process; Proteins; Receptor Signaling; Recruitment Activity; Recycling; Regulation; Risk; Role; Signal Transduction; Site; Smallpox; Syndrome; Systemic Lupus Erythematosus; T-Cell Receptor; Toll-like receptors; Tuberculosis; Vaccination; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; antigen processing; antigenic peptide transporter; autoreactivity; calreticulin; cost; cytotoxic; design; extracellular; insight; lupus-like; microbial; microorganism antigen; multicatalytic endopeptidase complex; pathogen; protein aminoacid sequence; public health relevance; receptor; response; scaffold; systemic autoimmune disease; tapasin; trafficking; vaccine development

 DESCRIPTION (provided by applicant): The classic pathway of major histocompatibility complex class I (MHC-I) presentation is important for activation of CD8 T cells, and relies primarily on shuttling cytosolic peptides into the endoplasmic reticulum (ER) lumen by the transporter associated with antigen processing (TAP). This critical role of TAP has made it a prime target for blockade by several human viruses and downregulation in many cancers as a mechanism of evading detection by cytotoxic CD8 T cells. There are, however, other mechanisms of MHC-I presentation that bypass TAP and activate TAP-independent CD8 T cell responses. One of these is cross-presentation, where dendritic cells present peptides derived from extracellular antigens. Although TAP can be important here, cross- presentation can also take place without TAP, but the pathways involved are poorly defined. There are many disease states that result from altered TAP function and their basis is not easily explained by impairment in classic MHC-I presentation. TAP polymorphisms are associated with an increased risk for systemic lupus erythematosus (SLE), a chronic and severe systemic autoimmune disease characterized by high titers of autoantibodies against cellular constituents. TAP mutations in humans lead to TAP deficiency syndrome where surprisingly patients do not exhibit particular susceptibility to viruses but rather suffer from chronic inflammation. Finally, the successful eradication of smallpox is attributed to vaccination with cowpox virus that was recently unexpectedly shown to block TAP. Over the years, we have made significant contributions to understanding the cell biology and regulation of antigen presentation. Using genetic, cell biological, and biochemical approaches, we will pursue 3 aims seeking to delineate the pathways of TAP-independent cross-presentation: Aim 1: We have found that MHC-I reside in special compartments within dendritic cells and their trafficking from these compartments to sites of microbial antigen is regulated by Toll-like receptors, which detect microbial components. We will study how absent TAP impacts the cellular localization and trafficking of MHC-I molecules. Aim 2: We have shown that Toll-like receptors favor the cross-presentation of microbial over self-antigens. We will investigate whether cross-presentation in the absence of TAP is subject to regulation by these receptors. Aim 3: We will study the cross-presentation of both infectious viral and non-infectious cellular antigens by virally infected dendritic cells wher TAP function is impaired. We would like to know whether cross- presentation can rescue MHC-I presentation of viral antigens by the very cells that are infected. We will also determine the ability of these infected cells to confine this presentation to viral and not cellular antigens. Or basic research here will enable us to identify critical points of regulation in the pathways of MHC-I presentation. We will then be able to design better vaccines for infectious diseases like malaria, tuberculosis or HIV that are best controlled by CD8 T cells. We will also be able to design strategies for intervention in autoimmune diseases like lupus where the presentation of cellular antigens is dysregulated.

 描述（由申请人提供）：主要组织相容性复合物 I 类 (MHC-I) 呈递的经典途径对于 CD8 T 细胞的激活非常重要，并且主要依赖于通过与抗原加工相关的转运蛋白 (TAP) 将胞质肽穿梭到内质网 (ER) 腔中。 TAP 的这一关键作用使其成为多种人类病毒阻断的主要目标，并作为逃避细胞毒性 CD8 T 细胞检测的机制在许多癌症中下调。然而，MHC-I 呈递的其他机制可以绕过 TAP 并激活不依赖 TAP 的 CD8 T 细胞反应。其中之一是交叉呈递，其中树突细胞呈递源自细胞外抗原的肽。尽管 TAP 在这里可能很重要，但交叉呈现也可以在没有 TAP 的情况下进行，但所涉及的途径尚不清楚。许多疾病状态是由 TAP 功能改变引起的，并且它们的基础不容易用经典 MHC-I 表现的损伤来解释。 TAP 多态性与系统性红斑狼疮 (SLE) 风险增加相关，SLE 是一种慢性、严重的系统性自身免疫性疾病，其特征是针对细胞成分的高滴度自身抗体。人类 TAP 突变会导致 TAP 缺乏综合征，令人惊讶的是，患者并未表现出对病毒特别敏感，而是患有慢性炎症。最后，成功根除天花要归功于牛痘病毒疫苗接种，最近出乎意料地显示牛痘病毒可以阻断 TAP。多年来，我们在理解细胞生物学和抗原呈递调节方面做出了重大贡献。使用遗传、细胞生物学和生化方法，我们将追求 3 个目标，试图描绘不依赖于 TAP 的交叉呈递途径： 目标 1：我们发现 MHC-I 驻留在树突状细胞内的特殊区室中，并且它们从这些区室到微生物抗原位点的运输受到 Toll 样受体的调节，Toll 样受体检测微生物成分。我们将研究 TAP 缺失如何影响 MHC-I 分子的细胞定位和运输。目标 2：我们已经证明，Toll 样受体比自身抗原更有利于微生物的交叉呈递。我们将研究在没有 TAP 的情况下交叉呈递是否受到这些受体的调节。目标 3：我们将研究 TAP 功能受损的病毒感染树突状细胞交叉呈递感染性病毒和非感染性细胞抗原。我们想知道交叉呈递是否可以挽救被感染细胞对病毒抗原的 MHC-I 呈递。我们还将确定这些受感染细胞将这种呈递限制于病毒而非细胞抗原的能力。 或者这里的基础研究将使我们能够确定 MHC-I 表达途径中的关键调节点。然后，我们将能够针对疟疾、结核病或艾滋病毒等传染病设计出更好的疫苗，这些疾病最好由 CD8 T 细胞控制。我们还将能够设计干预自身免疫性疾病的策略，例如狼疮，其中细胞抗原的表达失调。