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endopeptidase complex novel novel therapeutics novel vaccines peptide based vaccine response tool universal vaccine unpublished works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

建议总结