*3.2. Antigen Presentation by MHC Molecules*

The recognition of MHC I and II molecules is crucial for the communication that leads to DC-induced immune responses. The major MHC-dependent antigen process in DCs can be identified as followed: MHC II aids in the presentation of exogenous antigens internalized into DCs, whereas MHC I helps in the presentation of peptides generated from reprocessed proteins and peptides through proteasome-mediated degradation in the cytosol [59–61].

DCs provide pathogenic information that "alerts" the immune system to an infection by increasing MHC II production, or regulating MHC II degradation, by the following mechanisms [62]: (1) after synthesis in the endoplasmic reticulum (ER) of APCs, MHC II molecules are delivered to the plasma through the Golgi network, or by direct transport to late endosomal compartments, (2) plasma-loaded MHC II molecules internalize exogenous protein antigens by clathrin-mediated endocytosis [63], (3) the internalized antigenic proteins are processed to peptides via endosomal and lysosomal proteolysis, (4) the processed peptide molecules are then combined with MHC II on the late endosomal surface, and these immunodominant MHC II–peptide complexes migrate to the cellular surface membranes of APCs for identification by CD4<sup>+</sup> T lymphocytes, and the initiation of T helper immune responses [64,65], and (5) MHC II–peptide complexes are recycled through ubiquitination in proteasomes, and further degradation processes in lysosomes, until DC maturation is complete [66,67].

MHC I-mediated cross-presentation in the immune system occurs via immune proteasomes [68]. For the cross-presentation of exogenous TAAs using MHC I molecules: (1) exogenous antigenic proteins (such as viral proteins produced during infection) internalized by phagocytosis are transferred to proteasomes via the ubiquitin–proteasome pathway, and degraded by proteolytic enzymes; (2) the resulting peptides are transported into the ER by the transporter associated with antigen processing (TAP) [69] and an ATP-dependent transporter; (3) MHC I molecules are fabricated in the ER and connected with the TAP, and subsequent binding of MHC I to the transported peptides occurs; (4) MHC I–peptide complexes are then delivered to cell surface membranes for cross-presentation to activate antigen-specific CTLs; and (5) completely equipped CTLs kill prospective target cells, such as virus-infected cells or tumor cells [70]. Although it does not contribute as much as the proteasome pathway, the vacuolar pathway, which does not rely on proteasomes and TAP, also participates in cross-presentation via MHC I [71]: (1) internalized exogenous antigens are degraded by protein catabolism using cathepsin S as a protease within the endocytic compartment, (2) MHC I molecules are generated from the ER and transferred to the endosome, and (3) MHC I-containing endosomes are loaded with the peptides, and then, peptide–MHC I complexes are presented on the cellular plasma membrane [72].
