| Major Histocompatibilty Complex (MHC) class I typically presents peptide antigens (ags) derived from endogenously synthesized proteins. Dendritic cells (DCs), a subset of antigen presenting cells, experience a distinct maturational program that sequentially optimizes ag internalization, processing, and presentation. As these cells are essential for the effective priming of cytotoxic T cells, a unique pathway functioning in these cells allows the passive acquisition of pathogen-associated ags from infected cells and their presentation in the context of MHC class I. This pathway, termed cross presentation, allows the generation of cell-mediated immune responses against pathogens.;We have determined that, for efficient cross presentation, ags must first be internalized by constitutive endocytosis to enter peripheral endoplasmic reticulum (ER)-like compartments where they can be retrotranslocated into the cytosol by the sec6l pore. In addition to sec61, early phagosomes and macropinosomes from DCs contain the TAP transporter, the MHC class I loading complex, and associated proteasomes, making these peripheral vesicles sufficient to mediate all the events necessary for cross presentation. MHC class I molecules loaded in this compartment may either traffic directly to the cell surface or back to the ER for exocytic trafficking. A retrograde transport pathway, which may carry loaded phagosomal MHC class I molecules back to the ER, allows exogenous proteins to reach the perinuclear ER lumen. We have determined that, in DCs, a population of proteins introduced into this pathway could escape lysosomal proteolysis and enter the MHC class I loading pathway from this location. Peptide-loaded complexes are then released from TAP to exit the ER.;In immature DCs, assembled complexes are retained in the Golgi before reaching the cell surface, protecting these complexes from peptide exchange or degradation and preventing the inappropriate activation of T cell responses. Upon maturation, peptide-MHC class I complexes are rapidly relocalized to the cell surface for display to CD8+ T cells. Our characterization of this maturational control of MHC class I assembly and trafficking combined with the selective regulation of antigen internalization, retrograde trafficking to the ER lumen, protein retrotranslocation into the cytosol, costimulatory and adhesion molecule expression, and cellular morphology drastically explains the enhanced efficiency of cross presentation in DCs that facilitates their unique role in the induction of adaptive immune responses. |
