Mobilizing TAP-independent CD8 T cells through non-canonical cross-presentation

通过非规范交叉呈递动员不依赖 TAP 的 CD8 T 细胞

基本信息

批准号：
10659785
负责人：
Julie Magarian Blander
金额：
$ 67.69万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-05 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659785
关键词：
Animals Antigen Presentation Antigen Presentation Pathway Antigens CD8-Positive T-Lymphocytes Cell membrane Cell surface Cells Chronic Clinical Complex Cowpox virus Cross Presentation Cross-Priming Cytoplasm Dendritic Cells Development Endoplasmic Reticulum Endosomes Epithelial Cells Epitopes Etiology Family member Functional disorder Generations Golgi Apparatus Health Hematopoietic Herpesviridae Histocompatibility Antigens Class I Human Immune Immune Evasion Immune response Immune system Immunity Immunological Models Impairment Infection Location Lung Major Histocompatibility Complex Mass Spectrum Analysis Mediating Membrane Memory Modeling Monitor Mus Mutation Pathway interactions Peptides Phenotype Poxviridae Process Publishing Recrudescences Recycling Residual state Role SNAP receptor Site Smallpox T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire TAP1 gene TAP2 gene Testing Therapeutic Tissues Toll-like receptors Vaccine Design Variant Variola minor Viral Viral Antigens Viral Respiratory Tract Infection Virus Virus Diseases Work antigenic peptide transporter chronic infection cross immunity cytotoxic CD8 T cells design draining lymph node falls multicatalytic endopeptidase complex novel novel therapeutics novel vaccines peptide based vaccine response tool universal vaccine unpublished works

Animals Antigen Presentation Antigen Presentation Pathway Antigens CD8-Positive T-Lymphocytes Cell membrane Cell surface Cells Chronic Clinical Complex Cowpox virus Cross Presentation Cross-Priming Cytoplasm Dendritic Cells Development Endoplasmic Reticulum Endosomes Epithelial Cells Epitopes Etiology Family member Functional disorder Generations Golgi Apparatus Health Hematopoietic Herpesviridae Histocompatibility Antigens Class I Human Immune Immune Evasion Immune response Immune system Immunity Immunological Models Impairment Infection Location Lung Major Histocompatibility Complex Mass Spectrum Analysis Mediating Membrane Memory Modeling Monitor Mus Mutation Pathway interactions Peptides Phenotype Poxviridae Process Publishing Recrudescences Recycling Residual state Role SNAP receptor Site Smallpox T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire TAP1 gene TAP2 gene Testing Therapeutic Tissues Toll-like receptors Vaccine Design Variant Variola minor Viral Viral Antigens Viral Respiratory Tract Infection Virus Virus Diseases Work antigenic peptide transporter chronic infection cross immunity cytotoxic CD8 T cells design draining lymph node falls multicatalytic endopeptidase complex novel novel therapeutics novel vaccines peptide based vaccine response tool universal vaccine unpublished works

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项目摘要

PROPOSAL SUMMARY Major histocompatibility complex class I (MHC-I) molecules present peptides at the cell surface to CD8 T cells. The transporter associated with antigen processing (TAP) is a heterodimeric molecule of TAP1 and TAP2 that lies at the center of a macromolecular peptide loading complex tasked with loading and folding MHC-I molecules with peptides. TAP shuttles cytosolic proteasome-generated peptides across the membrane of the endoplasmic reticulum (ER) for luminal delivery and loading of MHC-I molecules. Given the crucial role of TAP in translocating peptides to MHC-I molecules, many clinically important human viruses such as Herpesviridae and Poxviridae have evolved strategies to block TAP and evade host CD8 T cell recognition. TAP blockade upon infection of dendritic cells (DC), which are responsible for naïve CD8 T cell priming, impairs conventional TAP-proteasome processing for the classic MHC-I presentation of peptides to CD8 T cells. In fact, the current paradigm holds that TAP blockade in DC renders these cells non-functional and incapable of priming a CD8 T cell response. Priming virus-specific CD8 T cells falls on uninfected TAP-sufficient bystander DC through cross-presentation, a process that enables MHC-I loading with viral peptides derived from DC internalized virus-infected dying cells. However, CD8 T cells primed by TAP-sufficient DC recognize dominant TAP-dependent peptides, whose presentation is severely reduced on tissues infected with immune evasive viruses. TAP-dependent CD8 T cells would also be mismatched to the TAP-independent peptides liberated by alternative TAP-independent processing of viral antigens and presented by MHC-I on those infected tissues. Either scenario creates a diminished or mismatched CD8 T cell target. How does the immune system get around this problem? We found that DC without functional TAP rely on cell-autonomous delivery of MHC-I from a new location, the ER-Golgi intermediate compartment (ERGIC), to internalized antigens to rescue MHC-I presentation and nevertheless cross-prime CD8 T cells. We call this pathway non-canonical cross-presentation. Our findings point to non-canonical cross-presentation as a previously unrecognized pathway for priming CD8 T cells that recognize TAP-independent epitopes and would be best-matched against immune evasive viruses. Studying non-canonical cross-presentation is important to understand the full spectrum of CD8 T cells that can be mobilized against infection, especially if such T cells provide potent local cross-protection within infected tissues. We seek to understand the role of non-canonical cross-presentation in priming a TAP-independent CD8 T cell response against viral infection. Using novel models, we will identify DC that conduct non-canonical cross-presentation, and define the repertoire of TAP-independent epitopes they present to antigen-specific TAP-independent CD8 T cells. We will create novel tools to track TAP- independent CD8 T cell responses and determine whether non-canonical cross-presentation can drive cross- protective immunity against viral variants and immune evasive viruses. Understanding non-canonical cross- presentation will inform universal vaccine design and new therapies for chronic and persistent viral infections.

提案摘要主要的组织相容性复合物I类（MHC-I）分子在细胞表面呈petides to CD8 T细胞。与抗原加工（TAP）相关的转运蛋白是TAP1和TAP2的异二聚体分子位于负载和折叠MHC-I分子的大分子肽加载复合物的中心有宠物。 Tap穿梭于内质的膜上的蛋白酶体生成的宠物网状（ER）用于MHC-I分子的腔内递送和负载。考虑到TAP在易位中的关键作用 MHC-1分子的肽，许多临床上重要的人类病毒，例如疱疹病毒和poxviridae 已经发展了阻止TAP并逃避主机CD8 T细胞识别的策略。感染后的Tap Bloskade 导致幼稚CD8 T细胞启动的树突状细胞（DC）会损害常规的Tap-proteasome 肽对CD8 T细胞的经典MHC-I表现的处理。实际上，当前的范式认为 DC中的TAP封锁使这些细胞无功能且无力启动CD8 T细胞反应。启动病毒特异性的CD8 T细胞通过交叉表达属于未感染的踢踏旁旁观者DC，这是一个过程这样可以使MHC-1用DC内部病毒感染的垂死细胞衍生的病毒petides加载。然而， CD8 T细胞由充满水龙头的直流识别的主要TAP依赖性肽，其表现为严重降低了感染免疫反射病毒的组织。 TAP依赖性CD8 T细胞也将是与无独立的无依赖性处理的病毒处理所释放的无依赖的宠物不匹配抗原并由MHC-1在那些感染的组织上提出。场景会造成降低或不匹配的情况 CD8 T细胞目标。免疫系统如何解决这个问题？我们发现DC无功能 TAP依靠MHC-I从新位置（ER-Golgi）中间室的细胞自主传递（ERGIC），以内部化抗原来挽救MHC-I的表现及其跨频率CD8 T细胞。我们称此途径非经典交叉呈递。我们的发现指出非经典交叉表达为以前无法识别的途径，用于识别独立表位的CD8 T细胞，并且将最好与免疫回避病毒匹配。研究非典型交叉表现对了解可以动员感染的CD8 T细胞的全光谱，尤其是在此类T细胞的情况下在感染组织中提供潜在的局部交叉保护。我们试图了解非典型的角色针对病毒感染的启动无依赖性的CD8 T细胞反应的交叉表达。使用新型模型，我们将确定执行非典型交叉呈现的DC，并定义无独立的曲目它们呈现给抗原特异性TAP独立的CD8 T细胞。我们将创建新颖的工具来跟踪Tap- 独立的CD8 T细胞反应，并确定非经典交叉呈现是否可以驱动交叉 - 防止病毒变异和免疫回避病毒的保护性免疫学。了解非典型的交叉演示将为慢性和持续性病毒感染的通用疫苗设计和新疗法提供信息。