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: 10413224
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413224
• 关键词: Address; Antigens; Autophagocytosis; Binding; Biological; 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; Play; Process; Proteins; Proteomics; Recycling; Repair Complex; Role; Route; T cell response; T-Lymphocyte; Testing; Viral Proteins; Virus; base; cytotoxic; cytotoxic CD8 T cells; dimer; discount; 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.

项目概要 病毒感染的细胞表达与病毒衍生肽相关的 MHC-I 分子， 被细胞毒性 CD8+ T 细胞识别。肽由蛋白酶体产生。 降解细胞质中合成的病毒蛋白并与组装 MHC-I 重链结合 然而，初始 CD8+ T 细胞中的链-β2 微球蛋白二聚体必须做好诱导准备。 成熟的细胞毒性表型通常由获得抗原的 DC 介导。 内吞作用和/或吞噬作用产生 MHC-I 结合肽，这一过程称为 交叉呈现的机制仍然知之甚少，只有 我们发现了一些效应器，但没有一个是绝对需要的，原因是： 没有单一的文献数据指向三个途径。 首先，吞噬溶酶体蛋白酶（组织蛋白酶）降解抗原以原位生成肽 这些通过肽交换与回收 MHC-I 结合，我们将其视为主要因素。 机制，因为它会导致 MHC-I-肽复合物之间的不匹配 通过交叉呈递产生的和最终细胞毒性中蛋白酶体产生的 CD8+ T 细胞的目标是病毒感染的细胞，第二个是吞噬或内吞抗原。 穿过吞噬体/内体膜转移到细胞质中，就像 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，这些肽被转移到 ER（或已募集的吞噬体）中。 ER 成分）通过与抗原加工 (TAP) 相关的转运蛋白并结合 组装 MHC-I 分子，然后将其运输到细胞表面。 确定从内吞区室到胞质溶胶的易位机制。 第三条途径，不是内化抗原进入细胞质，而是细胞质蛋白酶体 然后将抗原递送至吞噬体和/或内体的腔内进行加工。 蛋白酶体原位产生与再循环 MHC-I 结合的肽。 不依赖于抗原肽的 TAP 转运，但依赖于蛋白酶体活性。 我们建议交叉展示的第二条和第三条路线都可以操作， 共同点是终点，即 CD8+ T 细胞的抗原识别。 建立和维持成功的 CD8+ T 细胞反应所需的精确机制将是 决定。