370
Antigen Presenting Cells (APCs)
complexes to enter a multimolecular load-
ing complex, which is responsible for
the formation of cognate class I-peptide
complexes. Constituents of this loading
complex are
α
:
β
2m
, calreticulin, TAP, the
protein-disulFde-isomerase
ERp57,
and
the
TAP-associated
chaperone
tapasin
(±ig. 5). During peptide loading, ERp57
gives allowance for the regulated opening
and closing of a disulFde bond in the bind-
ing cleft domain of the class I heavy chain.
Tapasin bridges TAP and
α
:
β
2m
,andre
-
tains peptide-free
α
:
β
2m
dimers in the ER
until a stably binding peptide occupies the
groove. Consequently, preferentially long-
lived
α
:
β
2m
-peptide complexes leave the
ER and make it to the cell surface. Thus,
tapasin is thought to function as a peptide
editor, similar to HLA-DM in the MHC
class II processing pathway (see below).
6.2
MHC Class II Processing Pathways
MHC class II-associated peptides originate
from two sources: endocytosed exogenous
antigens
or
endogenous
self-antigens,
the majority of them being membrane
proteins derived from endosomes or the
nucleus (Table 4).
6.2.1
Endosomal Generation of Peptides
Professional APCs are equipped to in-
ternalize whole pathogens, for example,
bacteria or viruses, small vesicles, mul-
timolecular complexes, proteins or pep-
tides via phagocytosis, pinocytosis or in
a receptor-mediated fashion. In all these
cases, endocytosed antigens end up in en-
dosomal compartments, known for their
low pH and the high redox potential
(±ig. 5). These conditions favor denatura-
tion of protein antigens and proteolytic
generation of peptides via hydrolases,
amino- and carboxypeptidases, and en-
dopeptidases. Endosomal/lysosomal com-
partments of APCs, which are enriched in
MHC class II molecules, as determined
by electron microscopy or immunohis-
tochemically, have been termed
MIICs
(MHC class II compartments).
6.2.2
Invariant Chain and CLIP
The invariant chain (Ii) is a chaperone
dedicated
primarily
to
MHC
class
II
molecules. In DCs, Ii also binds to CD1
molecules. In general, Ii trimers bind to
newly synthesized class II
αβ
dimers,
allowing
them
to
obtain
their
native
conformation. Since Ii binding blocks
the sole peptide-binding cleft, Ii-associated
class II molecules cannot bind antigens.
Owing to a targeting signal in the cytosolic
tail of Ii, Ii class II complexes are sorted
from the trans-Golgi-network directly to
endosomal/lysosomal MIICs (±ig. 5).
In MIICs, Ii is proteolytically degraded
whereas
αβ
dimers remain intact. The
proteases mainly responsible for Ii degra-
dation are cathepsin S in DCs and B cells
and cathepsin L in cortical epithelial cells.
The terminal Ii fragment that still occu-
pies the peptide-binding cleft of class II
molecules is termed
CLIP
(class II MHC-
associated Ii peptide). Under steady state
conditions, CLIP is part of the self-peptide
repertoire of class II molecules. Since it
dissociates from the majority of class II
allelic proteins rather slowly, CLIP has
to be actively removed from the class II
binding cleft.
6.2.3
HLA-DM
HLA-DM (termed H2-M in mice) is a non-
classical MHC class II protein, displaying
20 to 25% sequence homology to both
classical class I and class II molecules. X-
ray analysis revealed that HLA-DM lacks
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