Endocytosed antigens must leave the endocytic structure to enter into the MHC I pathway before exhaustive degradation within lysosomes. The canonical pathway is the transporter associated with antigen processing (TAP)-dependent cytosolic pathway, which involves the translocation of endocytosed antigens into the cytosol where they are degraded into antigenic peptides by the proteasome and transported to ER through TAP. This hypothesis comes from indirect evidences showing that proteasome inhibitors block cross presentation of certain antigens (Amigorena et al. 2010, Burgdorf et al. 2008) . According to this model antigens are translocated into the cytosol by an undefined mechanism.
There are less well-characterized mechanisms for the delivery of exogenous antigens into the cytosol. Certain peptides with highly positively charged sequences derived from HIV tat protein or the Antennapedia homeodomain (AntHD) protein seem to penetrate into the cytosol directly across the plasma membrane (Monu et al. 2007, Vendeville et al. 2004). It is also proposed that some exogenous antigens can be exchanged between neighboring cells through gap junctions, leading to cross presentation by the recipient cell (Monu et al. 2007, Neijssen et al. 2005).
Once internalized antigens are routed into the cytosol, they follow the conventional pathway of proteasome digestion and TAP mediated transport of peptides into the ER lumen.