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CD 8 T细胞的活化是重要的，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的这种关键作用使其成为几种人类病毒阻断的主要靶标，并在许多癌症中下调，作为逃避细胞毒性CD 8 T细胞检测的机制。然而，存在绕过TAP并激活TAP非依赖性CD 8 T细胞应答的MHC-I呈递的其他机制。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。虽然TAP在这里可能很重要，但交叉呈递也可以在没有TAP的情况下发生，但所涉及的途径定义不清。许多疾病状态是由TAP功能改变引起的，其基础并不容易通过经典MHC-I表现的损伤来解释。TAP多态性与系统性红斑狼疮（SLE）的风险增加有关，SLE是一种慢性和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。人类的TAP突变导致TAP缺乏综合征，令人惊讶的是，患者对病毒没有表现出特别的易感性，而是患有慢性炎症。最后，天花的成功根除归功于牛痘病毒的接种，最近出乎意料地显示牛痘病毒可以阻断TAP。多年来，我们为理解细胞生物学和抗原呈递的调节做出了重大贡献。使用遗传学，细胞生物学和生物化学的方法，我们将追求3个目标，寻求描绘TAP独立的交叉呈递的途径：目的1：我们已经发现，MHC-I驻留在树突状细胞内的特殊隔室和它们的运输从这些隔室的微生物抗原的网站是由Toll样受体，检测微生物成分的调节。我们将研究缺少TAP如何影响MHC-I分子的细胞定位和运输。目的2：我们已经证明Toll样受体有利于微生物对自身抗原的交叉呈递。我们将调查是否在TAP的情况下交叉呈递受这些受体的调节。目标三：我们将研究TAP功能受损的病毒感染树突状细胞对感染性病毒和非感染性细胞抗原的交叉呈递。我们想知道交叉呈递是否可以拯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于病毒而非细胞抗原的能力。 或者基础研究将使我们能够确定MHC-I呈递途径中的关键调控点。然后，我们将能够设计出更好的疫苗，用于疟疾、结核病或艾滋病等传染病，这些疾病最好由CD 8 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，如狼疮，其中细胞抗原的呈递失调。