Some antigens are cross-presented through a vacuolar mechanism that involves generation of antigenic peptides and their loading on to MHC-I molecules within the endosomal compartment in a proteasome and TAP-independent manner. Antigens within the endosome are processed by cathepsin S and other proteases into antigenic peptides. Loading of these peptides onto MHC-I molecules occurs directly within early and late endosomal compartments. Why certain antigens are cross-presented exclusively by the cytosolic pathway while others use the vacuolar pathway is unknown. It may be because some epitopes cannot be generated by endosomal proteolysis, or are completely destroyed. Alternatively, the physical form of the antigen may influence its accessibility to the endosomal or vacuolar pathways (Shen et al. 2004).