Mechanisms of antigen cross-presentation by MHC class I molecules

项目摘要 受病毒感染的细胞表达与病毒衍生的多肽相关的MHC-I分子 被细胞毒CD8 T细胞识别。这些多肽是由蛋白酶体产生的 胞浆中合成的病毒蛋白的降解及其与MHC-I重组体的结合 内质网中的Chain-β2微球蛋白二聚体。然而，幼稚的CD8 T细胞必须准备好才能诱导 成熟的细胞毒性表型。启动通常由DC介导，DC通过以下途径获得抗原 吞噬作用和/或吞噬作用以产生MHC-I结合的多肽，这一过程称为 交叉演示。交叉呈现的机制仍然知之甚少，只有 确定了几个效应器，但不是绝对必需的。我们提出，原因是 不存在单一的交叉演示路径。文献数据指出了三条路径。在 首先，吞噬酶(组织蛋白)降解抗原，在原位产生多肽。 它们通过肽交换与循环MHC-I结合。我们认为这是个重大事件。 机制，因为它会导致MHC-I-肽复合体之间的不匹配 由交叉呈现产生的和由蛋白酶体产生的最终的细胞毒性 CD8T细胞为靶细胞，病毒感染细胞。在第二阶段，吞噬或内吞的抗原 通过吞噬体膜/内体膜转移到细胞质中，在那里， 病毒感染细胞中新合成的蛋白质，它们被胞浆蛋白酶体降解 以产生多肽。这些被转移到内质网(或已招募的吞噬体内 ER组分)通过与抗原处理相关的转运蛋白(TAP)并结合到 组装MHC-I分子，然后将其输送到细胞表面。我们建议 确定从胞内室到胞浆的转位机制(S)。在 第三条途径，而不是内化的抗原进入胞浆，胞浆蛋白酶体是 输送到吞噬小体和/或内小体的腔内。然后这些抗原被加工成 由蛋白酶体原位产生与循环MHC-I结合的多肽。这条路是 不依赖于抗原肽的TAP运输，但依赖于蛋白酶体的活性。 我们建议，第二条和第三条交叉陈述路线都可以运作， 公分母是终点，即CD8T细胞对抗原的识别。这个 安装和维持成功的CD8 T细胞反应所需的精确机制将是 下定决心。

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.