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endopeptidase complex novel novel therapeutics novel vaccines peptide based vaccine response tool universal vaccine unpublished works

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.

提案摘要主要组织相容性复合物 I 类 (MHC-I) 分子在细胞表面将肽呈递给 CD8 T 细胞。与抗原加工相关的转运蛋白 (TAP) 是 TAP1 和 TAP2 的异二聚体分子，位于大分子肽装载复合物的中心，负责装载和折叠 MHC-I 分子 TAP 使胞质蛋白酶体产生的肽穿过内质膜。鉴于 TAP 在易位中的关键作用，网状结构 (ER) 用于 MHC-I 分子的腔内递送和装载。 MHC-I 分子的肽，许多临床上重要的人类病毒，如疱疹病毒科和痘病毒科已经发展出阻断 TAP 并逃避宿主 CD8 T 细胞感染后 TAP 阻断的策略。树突状细胞 (DC) 负责初始 CD8 T 细胞启动，会损害传统的 TAP 蛋白酶体经典的 MHC-I 肽向 CD8 T 细胞呈递的处理事实上，当前的范例认为。 DC 中的 TAP 阻断使这些细胞失去功能并且无法启动 CD8 T 细胞反应。病毒特异性 CD8 T 细胞通过交叉呈递过程落在未感染的 TAP 充足的旁观 DC 上这使得 MHC-I 能够装载来自 DC 内化病毒感染的垂死细胞的病毒肽。由 TAP 充足的 DC 引发的 CD8 T 细胞识别主要的 TAP 依赖性肽，其呈现形式为感染免疫逃避病毒的组织中依赖 TAP 的 CD8 T 细胞也会严重减少。与病毒的替代 TAP 独立加工释放的 TAP 独立肽不匹配抗原并由受感染组织上的 MHC-I 呈递，这两种情况都会导致抗原减少或不匹配。 CD8 T 细胞目标。免疫系统如何解决这个问题？我们发现 DC 没有功能？ TAP 依赖于细胞自主从新位置（ER-高尔基体中间室）输送 MHC-I (ERGIC)，内化抗原以拯救 MHC-I 呈递并交叉引发 CD8 T 细胞。我们的研究结果表明，非规范交叉呈现是一种非规范交叉呈现。以前未被识别的启动 CD8 T 细胞的途径，这些细胞识别 TAP 独立表位，并且会研究非规范交叉呈现对于免疫逃避病毒来说非常重要。了解可以动员起来抵抗感染的全谱 CD8 T 细胞，特别是如果这些 T 细胞在受感染的组织内提供有效的局部交叉保护我们试图了解非规范的作用。使用新模型交叉呈递来引发不依赖于 TAP 的 CD8 T 细胞反应。我们将识别进行非规范交叉表示的 DC，并定义独立于 TAP 的曲目它们向抗原特异性 TAP 独立的 CD8 T 细胞呈递表位，我们将创建新的工具来追踪 TAP- 独立的 CD8 T 细胞反应并确定非典型交叉呈递是否可以驱动交叉了解针对病毒变种和免疫逃避病毒的保护性免疫力。演讲将为通用疫苗设计和慢性和持续性病毒感染的新疗法提供信息。