Processing af
Extracellular Antigen For Class II MHC Presentation Follows a Different Pathway
Class II MHC complexes with
antigenic peptide are generated
by a fundamentally different
intracellular mechanism, as the
APCs that interact with
T‐helper cells need to sample the
antigen from the extracellular compartment. In essence, a trans‐Golgi vesicle containing MHC class II has to meet up with a late
endosome containing exogenous protein antigen taken into the cell by
phagocytosis, macropinocytosis, or endocytosis.
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Figure 5.16 Processing of exogenous antigen and presentation by class II MHC. Class
II molecules with Ii are assembled (actually as a nonamer consisting of three
invariant, three class II α, and three class II β chains – not shown) in the
endoplasmic reticulum (ER). They are then transported through the Golgi to the
trans‐Golgi reticulum The class II‐containing vacuole now fuses with a late
endosome which has lysosomal characteristics and contains peptides generated by
partial degradation of proteins derived from the endocytic uptake of exogenous
antigen. This fusion generates a so‐called MHC class II‐enriched compartment,
MIIC. Particularly implicated in the processing of exogenous antigen in the
endosomes are the cysteine proteases cathepsin S and L, both of which have
endopeptidase activity, as do both cathepsin D and asparagine endopeptidase
(AEP) which might also partake in this process. Subsequently, the exopeptidases
cathepsin B and X are thought to trim the C‐terminus, and cathepsins C and H to
trim the N‐terminus of the peptides either prior to or after their binding into
the MHC class II groove. Degradation of the invariant chain leaves the CLIP
(class II‐associated invariant chain peptide) lying in the groove but, under
the influence of the DM molecule, this is replaced by the peptides derived from
exogenous antigen, and the complexes are transported to the cell surface for presentation to
T‐helper cells.
Regarding the class II
molecules themselves, these are assembled from α and β chains in the ER in
association with the transmembrane invariant chain (Ii) (Figure
5.16), which trimerizes to recruit three MHC class II molecules into a
nonameric complex. Ii has several functions. First, it acts as a dedicated chaperone
to ensure correct folding of the nascent class II molecule. Second, an
internal sequence of the luminal portion of Ii sits in the MHC groove to
inhibit the precocious binding of peptides in the ER before the class II
molecule reaches the endocytic compartment containing antigen. Additionally,
combination of Ii with the αβ class II heterodimer inactivates a
retention signal and allows transport to the Golgi. Finally, targeting
motifs in the N-terminal cytoplasmic region of Ii ensure
delivery of the class II‐containing vesicle to the endocytic pathway.
Meanwhile, exogenous protein
is taken up by one of the endocytic processes referred to above. The enzyme GILT
(interferon‐γ‐induced lysosomal thiol reductase) is present in the
endosomes and will break any disulfide bonds that are present in the engulfed
proteins. As the early endosome undergoes progressive acidification, the
proteins are processed into peptides by a range of proteolytic enzymes (see
Figure 5.16 legend). The early endosomes mature into late endosomes and
lysosomes, both of which characteristically acquire lysosomal‐associated
membrane proteins (LAMPs), including the LAMP‐2a receptor
for chaperone‐mediated autophagy. These late endosomes fuse with the vacuole
containing the class II–Ii complex. Under the acidic conditions within these
MHC class II‐enriched compartments (MIICs), asparagine endopeptidase (AEP) and
cathepsins S, L, and F degrade Ii except for the part sitting in the MHC groove
that, for the time being, remains there as a peptide referred to as CLIP (class
II‐associated invariant chain peptide). An MHC‐related heterodimeric molecule,
DM, then catalyzes the removal of CLIP and keeps the groove open so that pep-
tides generated in the endosome can be inserted (Figure 5.17). Initial peptide
binding is determined by the concentration of the peptide and its on‐rate, but
DM subsequently assists in the removal of lower affinity peptides to allow
their replacement by high‐affinity peptides (i.e., acts as a peptide editor
permitting the incorporation of peptides with the most stable binding
characteristics, namely those with a slow off rate).
Particularly in B‐cells and thymic epithelium, an additional MHC‐related
heterodimeric molecule, DO, associates with DM bound to class II and inhibits
its function. The precise role of DO remains elusive. However, in B‐cells it
may transiently restrain DM in order to favor the presentation of antigens
internalized via the BCR over those taken up by fluid phase endocytosis. The
class II–peptide complexes are then transported to the membrane for
presentation to T‐helper cells.
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Figure 5.17 MHC class II transport and
peptide loading illustrated by Tulp’s gently vulgar cartoon.
