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. Author manuscript; available in PMC: 2019 Apr 26.
Published in final edited form as: Annu Rev Immunol. 2018 Feb 28;36:717–753. doi: 10.1146/annurev-immunol-041015-055523

Figure 4.

Figure 4

The different subcellular sources of MHC-I molecules for cross-presentation. Published evidence supports the use of four distinct sources of MHC-I for cross-presentation by dendritic cells (DCs): (1) the endoplasmic reticulum (ER), (2) the trans-Golgi network (TGN), (3) the plasma membrane, and (4) the endosomal recycling compartment (ERC). (1) Direct trafficking of MHC-I molecules from the ER to endolysosomal compartments has been reported in bone marrow–derived DCs mediated by the chaperone CD74, which associates with MHC-I molecules and chaperones them to late endosomal compartments marked by LAMP-1. This compartment may contain endocytosed antigen delivered from the plasma membrane. Deficiency in CD74 impairs cross-presentation, suggesting that in this case ER-delivered MHC-I and not plasma membrane MHC-I is loaded within the late endosomal/lysosomal compartment, from which they may traffic directly to the plasma membrane for recognition by CD8 T cells. (2) The secretory pathway of newly synthesized MHC-I molecules (see Figure 1) is diverted by MARCH9-mediated ubiquitination of MHC-I in the TGN and their diversion via SCAMP3+ vesicles to multivesicular bodies (MVBs) (perhaps for degradation) or syntaxin-6+ vesicles to late endosomes (perhaps for loading with antigen delivered from the sorting endosome). (3) A tyrosine residue at position 320 (Y320) within the MHC-I cytoplasmic domain is critical for delivery of MHC-I to endosomal cross-presentation compartments, where peptide loading presumably takes place. Y320 might traffic MHC-I from the Golgi compartment to late endosomes, similar to its role in trafficking MHC-I from the plasma membrane to late endosomes, perhaps during clathrin-independent endocytosis. The ER, TGN, and plasma membrane sources of MHC-I are presumably used preferably for the cross-presentation of endocytic antigen, but this remains to be formally tested. (4) During phagocytosis, plasma membrane MHC-I might become internalized as phagosomes form, but when cargo such as a bacterium carries TLR ligands, additional numbers of MHC-I are recruited from the MHC-I-rich ERC under control of TLR-MyD88-IKK2 signaling (designated in blue letters). This mobilization serves to augment cross-presentation by increasing the number of ERC-resident MHC-I molecules available for loading with bacterial peptides. It is assumed that loading takes place in the phagosome followed by export of peptide-MHC-I complexes to the plasma membrane.