Mechanisms of antigen cross-presentation by MHC class I molecules

MHC I 类分子的抗原交叉呈递机制

• 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
• 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

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.

项目摘要 病毒感染的细胞表达与病毒衍生肽相关的MHC-1分子 通过细胞毒性CD8+ T细胞识别。肽是由蛋白酶体产生的 在细胞质中合成的病毒蛋白的降解并结合组装MHC-I重物 ER中的链-β2Microglobolin二聚体。但是，必须启动幼稚的CD8+ T细胞以诱导 成熟的细胞毒性表型。启动通常是由DC介导的，DC通过 内吞作用和/或吞噬作用以生成MHC-I结合的Pepperides，这一过程称为 交叉表现。交叉陈述的机制仍然很少了解，只有 确定了一些效果，绝对不需要。我们建议原因是 没有一个交叉呈递途径。文献数据指向三个途径。在 首先，吞噬蛋白酶（组织蛋白酶）降解抗原以产生辣椒原位 这些通过胡椒交换结合到回收MHC-I。我们将其视为专业 机理，因为它会导致MHC-I肽复合物之间的不匹配 由交叉呈递产生以及由蛋白酶体在最终细胞毒性中产生的。 CD8+ T细胞靶标，病毒感染细胞。在第二个，吞噬或内吞抗原 在吞噬体/内体膜上转移到细胞质中， 在病毒感染细胞中新合成的蛋白质，它们被胞质蛋白酶体降解 生成肽。这些被易位到ER（或已招募的吞噬体 ER组件）通过与抗原处理（TAP）相关的转运蛋白，并与 组装MHC-I分子，然后将其转运到细胞表面。我们建议 确定从内吞区室到细胞质的易位机制。在 第三个途径，而不是进入细胞质的内部抗原，而是胞质蛋白酶体是 输送到吞噬体和/或内体的腔内。然后在 蛋白酶体的原位产生与回收MHC-I结合的肽。这条路是 独立于抗原宠物的龙头转运，但取决于蛋白酶体的活性。 我们建议第二和第三个交叉表达的路线都可以运行， 共同点是终点，即CD8+ T细胞识别抗原。这 安装和维持成功的CD8+ T细胞响应所需的精确机制将是 决定。

项目成果

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)
• 作者: Sengupta,Debrup;Galicia-Pereyra,Rodrigo;Han,Patrick;Graham,Morven;Liu,Xinran;Arshad,Najla;Cresswell,Peter
• 通讯作者: Cresswell,Peter