Cross - Presentation of Antigens
We have just seen how MHC class I presents endogenous anti- gen while MHC class II presents exogenous antigen. However, between 10–30% of class I molecules present antigen of exogenous origin and a similar proportion of MHC class II molecules present peptides derived from either cytoplasmic or nuclear antigens. Indeed, naive cytotoxic T‐cells require dendritic cells for their activation but most viruses are not tropic for dendritic cells and therefore not naturally present in the cytosol of the professional APCs.
Given the two separate pathways (endogenous/class I, exogenous/class II) outlined in the previous sections, how can this be achieved? The answer to this conundrum lies in the phenomenon of cross‐presentation. Phagocytosed or endocytosed antigens can sneak out through channels in the vacuole into which they have been engulfed and thereby gain entry to the cytosol (Figure 5.18a). Once they enter the cytosol they are fair game for ubiquitination and sub-sequent degradation by the proteasome, followed by TAP‐mediated transfer into the ER, and presentation by MHC class I. It is also possible that some endocytosed antigens can be processed into peptides that are short enough to be loaded directly into recycling MHC class I molecules within the endosome without the need to be first processed in the cytosol. In addition to dendritic cells, macrophages also seem to be able to play the cross‐presentation game, albeit less efficiently.
Figure 5.18 Cross‐presentation of antigen. (a) Engulfed exogenous antigens are able to access the class I processing pathway by exiting the late endosomes and the MHC class II compartments (MIIC) through escape channels. Other routes for the presentation by MHC class I of peptides derived from exogenous antigens may include peptide exchange with MHC class I molecules recycling from the cell membrane. (b) Cross‐presentation can also work the other way round with cytosolic peptides generated from the proteasome (and also intact endogenous antigens) undergoing autophagy to gain entry into the class II processing and presentation pathway. ER, endoplasmic reticulum; TAP, transporter associated with antigen processing.
Conversely, some of the proteasome‐derived peptides within the cytosol, such as those derived from viral capsids, are of sufficient length to make them potential clients for the class II groove and could make the journey to the MIIC. This can occur by a process known as autophagy, in which portions of cytoplasm, which can contain peptides generated from the proteasome as well as intact proteins, are engulfed internally by structures referred to as autophagosomes (Figure 5.18b). Autophagy occurs constitutively in professional APCs and the peptide‐containing autophagosome can then fuse with the MHC class II‐containing MIIC, where proteolytic cleavage of any intact proteins could also take place. From then on events parallel those described for the presentation of exogenous anti-gens, with the peptides exchanging with CLIP, and transfer of peptide–MHC to the cell surface. During periods of cell stress a second pathway, chaperone‐mediated autophagy, can be employed involving members of the heat‐shock protein 70 (hsp70) family that bind to the protein to be processed. The protein complex is then recognized by LAMP‐2a and dragged into the lumen of a lysosome for subsequent processing.