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.
