树突状细胞（DC）通过MHC-I分子的交叉呈递向CD8T细胞表现内化抗原。尽管传统的cDC1擅长交叉呈递，但cDC2可以通过炎性受体信号（尤其是Toll样受体（TLRs））处于授权状态下进行交叉呈递。在TLRs控制的交叉呈递调节核心是对亚细胞分布的MHC-I的控制。在DC中，MHC-I富集于内质网回收室（ERC）并受噬菌体隔室化的TLR信号控制，以促进CD8T细胞基因引导到微生物抗原。病毒阻断与抗原处理相关的运输体（TAP）会耗尽ERC存储的MHC-I，从而同时阻止TLR调节的交叉呈递。DC通过启动非经典交叉呈递来抵消CD8T细胞主要的MHC-I呈递途径的两种不良影响，该途径将MHC-I从内质网 - 坡口体中新位置交付到噬菌体中，在TAP阻断时会异常地积累。非经典交叉呈递从而拯救了MHC-I的呈递，并对与免疫逃避病毒感染的靶细胞最匹配的TAP独立CD8T细胞进行基因调控。因为非经典交叉呈递依赖于MHC-I的噬菌体递送路线，而这种路线不受TLR控制，因此在感染期间存在自身抗原的潜在交叉呈递风险。在这里，我回顾了这些发现，以说明MHC-I的亚细胞路线如何关键地影响交叉呈递的调节以及CD8T细胞对感染和癌症的应答性质。我还强调了对CD8T细胞疫苗和免疫疗法的重要和新颖影响。版权所有© 2023 Elsevier Ltd. 保留所有权利。

Dendritic cells (DCs) present internalized antigens to CD8 T cells through cross-presentation by major histocompatibility complex class I (MHC-I) molecules. While conventional cDC1 excel at cross-presentation, cDC2 can be licensed to cross-present during infection by signals from inflammatory receptors, most prominently Toll-like receptors (TLRs). At the core of the regulation of cross-presentation by TLRs is the control of subcellular MHC-I traffic. Within DCs, MHC-I are enriched within endosomal recycling compartments (ERC) and traffic to microbe-carrying phagosomes under the control of phagosome-compartmentalized TLR signals to favor CD8 T cell cross-priming to microbial antigens. Viral blockade of the transporter associated with antigen processing (TAP), known to inhibit the classic MHC-I presentation of cytoplasmic protein-derived peptides, depletes the ERC stores of MHC-I to simultaneously also block TLR-regulated cross-presentation. DCs counter this impairment in the two major pathways of MHC-I presentation to CD8 T cells by mobilizing noncanonical cross-presentation, which delivers MHC-I to phagosomes from a new location in the ER-Golgi intermediate compartment (ERGIC) where MHC-I abnormally accumulate upon TAP blockade. Noncanonical cross-presentation thus rescues MHC-I presentation and cross-primes TAP-independent CD8 T cells best-matched against target cells infected with immune evasive viruses. Because noncanonical cross-presentation relies on a phagosome delivery route of MHC-I that is not under TLR control, it risks potential cross-presentation of self-antigens during infection. Here I review these findings to illustrate how the subcellular route of MHC-I to phagosomes critically impacts the regulation of cross-presentation and the nature of the CD8 T cell response to infection and cancer. I highlight important and novel implications to CD8 T cell vaccines and immunotherapy.Copyright © 2023 Elsevier Ltd. All rights reserved.