MHC class I endosomal and lysosomal trafficking coincides with exogenous antigen loading in dendritic cells.
BACKGROUND
Cross-presentation by dendritic cells (DCs) is a crucial prerequisite for effective priming of cytotoxic T-cell responses against bacterial, viral and tumor antigens; however, this antigen presentation pathway remains poorly defined.


RESULTS
In order to develop a comprehensive understanding of this process, we tested the hypothesis that the internalization of MHC class I molecules (MHC-I) from the cell surface is directly involved in cross-presentation pathway and the loading of antigenic peptides. Here we provide the first examination of the internalization of MHC-I in DCs and we demonstrate that the cytoplasmic domain of MHC-I appears to act as an addressin domain to route MHC-I to both endosomal and lysosomal compartments of DCs, where it is demonstrated that loading of peptides derived from exogenously-derived proteins occurs. Furthermore, by chasing MHC-I from the cell surface of normal and transgenic DCs expressing mutant forms of MHC-I, we observe that a tyrosine-based endocytic trafficking motif is required for the constitutive internalization of MHC-I molecules from the cell surface into early endosomes and subsequently deep into lysosomal peptide-loading compartments. Finally, our data support the concept that multiple pathways of peptide loading of cross-presented antigens may exist depending on the chemical nature and size of the antigen requiring processing.


CONCLUSIONS
We conclude that DCs have 'hijacked' and adapted a common vacuolar/endocytic intracellular trafficking pathway to facilitate MHC I access to the endosomal and lysosomal compartments where antigen processing and loading and antigen cross-presentation takes place.
Basha
Genc
G
Biomedical Research Centre, Michael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Lizée
Gregory
G
Reinicke
Anna T
AT
Seipp
Robyn P
RP
Omilusik
Kyla D
KD
Jefferies
Wilfred A
WA
D020816:Amino Acid Motifs; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D005805:Genes, MHC Class I; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D014617:Vacuoles / Q000378:metabolism