MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

• DOI: 10.1371/journal.pone.0003247
• Publication Date: 2008-09-18T17:06:47Z
• Authors: Genc Basha; Gregory Lizée; Anna T. Reinicke; Robyn P. Seipp; Kyla D. Omilusik; Wilfred A. Jefferies
• Keywords: Antigen Presentation; Cytoplasm; 0303 health sciences; Science; Q; Amino Acid Motifs; R; Genes, MHC Class I; Mice, Transgenic; Dendritic Cells; Endosomes; Endocytosis; Protein Structure, Tertiary; Mice; 03 medical and health sciences; Vacuoles; Medicine; Animals; Lysosomes; Research Article; Cell Proliferation; T-Lymphocytes, Cytotoxic

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.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.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.