394
Antigen Presenting Cells (APCs)
10.4
Antigen Processing and Presentation
10.4.1
Classical and Cross-presentation
via MHC Class I
Like other APCs and other nucleated cells,
DCs present self- or virus-derived en-
dogenous antigens to CD8
+
CTLs in an
MHC class I–restricted manner. In con-
trast to other cells, DCs express low levels
of the immunoproteasome already in the
immature state and upregulate it upon
maturation. Moreover, the abundance of
MHC class I–peptide complexes increases
during maturation. However, in contrast
to the MHC class II pathway, mature DCs
still synthesize and replace surface MHC
class I molecules in their mature state.
This Fnding raises the question, whether
DCs that have captured a class I–restricted
antigen in peripheral tissues, are the same
DCs that will present this antigen to CD8
+
T cells in secondary lymphoid organs.
Alternatively, DCs may capture antigens
in the lymph node. In this case, DCs
should be able to take up exogenous anti-
gen and transfer it onto MHC class I
molecules. This nonclassical mechanism
had already been proposed by Bevan and
colleagues: they showed that priming of
CTL responses
in vivo
can occur after pre-
sentation of exogenous antigens by class I
MHC molecules. These phenomena were
referred to as
cross-presentation
of antigen
and
cross-priming
of CD8
+
T cells.
In the meantime, cross-presentation has
been shown to be a major pathway utilized
by DCs in the context of various sources
of exogenous antigens. Physiologically,
phagocytosis appears to be a major route
for antigen uptake and cross-presentation,
as ±cR-mediated uptake of immune com-
plexes or opsonized dead cells promotes
cross-priming. ±urthermore, phagocyto-
sis of bacteria, bacteria-derived antigens,
and
apoptotic
cells
results
in
cross-
presentation of bacterial antigens and the
same has been observed for viral and tu-
mor antigens. Likewise, peptides bound
to Hsps, including gp96, Hsp90, Hsp60,
and Hsc70, are cross-presented by ma-
ture DCs.
Two
pathways for cross-presentation
were reported: the Frst foresees peptide
loading in the endocytic system, and hence
is
TAP-
and
proteasome-independent.
Recycling MHC class I molecules are,
indeed, found in endosomes of immature
DCs,
where
low
pH
is
supposed
to
favor exchange of prebound peptide for
exogenous peptide. The second pathway
is TAP-dependent and was reported in
DCs
in
several
experimental
settings.
This pathway foresees the existence of a
membrane transport system linking the
lumen of endosomes and the cytosol.
Other cells, for example, thymic epithelia
cells or liver sinusoidal epithelial cells,
are also able to present soluble exogenous
antigen in a TAP-dependent fashion, albeit
less efFciently than DCs.
As
an
alternative
to
explain
cross-
presentation, one could envisage that ER
compartments fuse with nascent endoso-
mal membranes before endosomes sepa-
rate from the plasma membrane, as most
recently shown for macrophages. This
would allow loading of exogenous anti-
gens onto MHC class I molecules in the
ER without the need for a specialized trans-
porter in the endosomal membrane. Phys-
iologically, this mechanism could serve to
feed the plasma membrane with phospho-
lipids from the ER to compensate the loss
of membranes due to endocytosis.
10.4.2
MHC Class II–restricted Antigen
Presentation
The cell surface display of MHC class
II–peptide complexes is tightly regulated
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