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.

项目摘要 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CD 8 + T细胞识别。这些肽由蛋白酶体产生， 降解细胞质中合成的病毒蛋白并结合组装的MHC-I重链 ER中β 2链微球蛋白二聚体。然而，幼稚的CD 8 + T细胞必须被引发以诱导 成熟的细胞毒性表型。致敏通常由DC介导，DC通过以下途径获得抗原： 通过内吞作用和/或吞噬作用产生MHC-I结合的肽，这一过程被称为 交叉展示交叉呈递的机制仍然知之甚少， 确定了一些效应器，但没有一个是绝对需要的。我们认为原因在于， 没有单一的交叉呈递途径。文献数据指出了三种途径。在 首先，吞噬溶酶体蛋白酶（组织蛋白酶）降解抗原以原位产生肽 它们通过肽交换与再循环MHC-I结合。我们把它作为一个主要的 因为它会导致MHC-I-肽复合物之间的错配 产生的交叉呈递和蛋白酶体产生的最终细胞毒性 CD 8 + T细胞是病毒感染的靶细胞。第二种是吞噬或内吞抗原 被转移穿过吞噬体/内体膜进入胞质溶胶， 在病毒感染的细胞中新合成的蛋白质，它们被胞质蛋白酶体降解 以产生肽。这些被转移到ER（或已经招募的吞噬体）中， ER组分）通过与抗原加工（TAP）相关的转运蛋白结合，并结合至 组装MHC-I分子，然后将其运输到细胞表面。我们建议 确定从内吞区室到胞质溶胶的易位机制。在 第三种途径，而不是内化抗原进入胞质溶胶，胞质蛋白酶体是 递送到吞噬体和/或内体的内腔中。然后将抗原在 通过蛋白酶体原位产生结合再循环MHC-I的肽。该途径 独立于抗原肽的TAP转运，但依赖于蛋白酶体活性。 我们建议，第二和第三路线的交叉介绍都可以运作， 共同点是终点，即CD 8 + T细胞的抗原识别。的 建立和维持成功的CD 8 + T细胞反应所需的精确机制将是 测定