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Mechanisms of antigen cross-presentation by MHC class I molecules

MHC I 类分子的抗原交叉呈递机制

基本信息

批准号：
10624950
负责人：
PETER CRESSWELL
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624950
关键词：
Address Antigens Autophagocytosis Binding Biological Biotinylation CD8-Positive T-Lymphocytes CD8B1 gene CRISPR library Candidate Disease Gene Cathepsins Cell surface Cells Complex Cross Presentation Cytosol Data Dendritic Cells Development Effector Cell Endocytosis Endosomes Enzymes Equilibrium Extravasation Genes Histocompatibility Antigens Class I In Situ Integral Membrane Protein Label Laboratories Literature Mediating Membrane Minor Molecular Pathway interactions Peptide Hydrolases Peptides Phagocytosis Phagosomes Phenotype Process Protein Biosynthesis Proteins Proteomics Recycling Repair Complex Role Route T cell response T-Lymphocyte Testing Viral Proteins Virus cytotoxic cytotoxic CD8 T cells dimer discount endosome membrane experimental study lipid transfer protein multicatalytic endopeptidase complex peptide I recruit repaired screening small hairpin RNA

项目摘要

Project Summary Virus infected cells express MHC-I molecules associated with virus-derived peptides that are recognized by cytotoxic CD8+ T cells. The peptides are generated by proteasomal degradation of viral proteins synthesized in the cytosol and bind to assembling MHC-I heavy chain-β2microglobulin dimers in the ER. Naïve CD8+ T-cells, however, must be primed to induce a mature cytotoxic phenotype. Priming is generally mediated by DCs that acquire antigens by endocytosis and/or phagocytosis to generate the MHC-I-bound peptides, a process called cross-presentation. The mechanisms of cross-presentation remain poorly understood, with only a few effectors identified and none are absolutely required. We propose that the reason is that there is not a single cross-presentation pathway. Literature data points to three pathways. In the first, phagolysosomal proteases (cathepsins) degrade antigens to generate the peptides in situ and these bind to recycling MHC-I by peptide exchange. We discount this as a major mechanism because it would result in a mismatch between the MHC-I-peptide complexes generated by cross-presentation and those generated by proteasomes in the ultimate cytotoxic CD8+ T cell target, the virus infected cell. In the second, phagocytosed or endocytosed antigens are transferred across phagosomal/endosomal membranes into the cytosol where, like the newly synthesized proteins in virus infected cells, they are degraded by cytosolic proteasomes to generate peptides. These are translocated into the ER (or phagosomes that have recruited ER components) by the Transporter associated with Antigenic Processing (TAP) and bind to assembling MHC-I molecules, which are then transported to the cell surface. We propose to determine the mechanism(s) of translocation from endocytic compartments to the cytosol. In the third pathway, rather than internalized antigens entering the cytosol, cytosolic proteasomes are delivered into the lumen of phagosomes and/or endosomes. The antigens are then processed in situ by the proteasomes to generate peptides that bind to recycling MHC-I. This pathway is independent of TAP transport of the antigenic peptides but is dependent on proteasome activity. We propose that the second and third routes of cross-presentation can both operate, the common denominator being the endpoint, namely antigen recognition by the CD8+ T cells. The precise mechanisms required to mount and maintain a successful CD8+ T cell response will be determined.

项目总结

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cutting Edge: Phagosome-associated Autophagosomes Containing Antigens and Proteasomes Drive TAP-Independent Cross-Presentation.

最前沿：含有抗原和蛋白酶体的吞噬体相关自噬体驱动不依赖于 TAP 的交叉呈递。

DOI：
10.4049/jimmunol.2200446
发表时间：
2024
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Sengupta,Debrup;Galicia-Pereyra,Rodrigo;Han,Patrick;Graham,Morven;Liu,Xinran;Arshad,Najla;Cresswell,Peter
通讯作者：
Cresswell,Peter