368
Antigen Presenting Cells (APCs)
respective cells present viral peptide anti-
gens bound to MHC class I molecules
on their cell surface. Likewise, exoge-
nous foreign antigens that are pino- or
phagocytosed by APCs at sites of in-
flammation lead to activation of CD4
+
helper T cells when APCs present antigen-
derived peptides in the context of MHC
class II molecules. The concept that for-
eign antigenic peptides stimulate T cells
only in the context of MHC molecules
has been introduced by Zinkernagl and
Doherty as
MHC restriction
.Theconve
r
-
sion of protein antigens derived from
the extracellular space or the cytosol into
peptides and the conservation of this anti-
genic information through loading onto
MHC class II or class I molecules is
accomplished
by
pathways
of
antigen
processing.
The different fates of vesicular and
cytosolic
antigens
are
mainly
due
to
the segregated pathways of biosynthesis
and assembly of class I and class II
molecules. Both pathways, however, have
evolved as adaptations of basic cellular
functions, such as endocytosis, transmem-
brane transport, and protein degradation,
which are not exclusively used for antigen
presentation.
6.1
MHC Class I Processing Pathways
The peptide-receptive binding cleft of class
I molecules is localized on the lumi-
nal side of the ER. Class I–restricted
antigenic peptides, however, are derived
from cytosolic or nucleic protein anti-
gens. Therefore, accessory molecules are
necessary for antigen processing. IFN-
γ
increases the expression of these acces-
sory molecules and MHC class I molecules
(Fig. 5).
6.1.1
Generation of Peptide Ligands
The majority of antigenic peptides pre-
sented by MHC class I molecules appears
to be generated by the multicatalytic pro-
teinase complex, named the proteasome.
The proteasome is localized in the cytosol
and nucleus and consists of 28 subunits
that form a central channel where un-
folded polypeptides are cleaved into short
peptides (Fig. 5). In the presence of IFN-
γ
, the catalytic activity of the proteasome
changes due to the replacement of 3 con-
stitutive subunits for the new subunits
LMP2, LMP7, and MECL-1. The protea-
some containing these new subunits is
called the immunoproteasome and prefer-
ably generates peptides with a C-terminal
hydrophobic or basic amino acid. Peptides
with these structural features are superior
to other peptides with regard to binding to
MHC class I molecules.
Apart from the proteasome, other pro-
teases and peptidases are involved in
processing of antigens in the MHC class I
pathway: cytosolic calpains and aminopep-
tidases are sometimes required, the actual
involvement being
strongly
influenced
b
yt
h
et
y
p
eo
fa
n
t
i
g
e
nt
ob
ec
l
e
a
v
e
d
.
Moreover, the ER-resident aminopepti-
dase ERAP-1 has recently been described
to be mainly responsible for N-terminal
trimming of precursor peptides, thereby
giving rise to typical 8-mer, 9-mer, and
10-mer epitopes.
6.1.2
TAP
The transporter associated with antigen
processing (TAP) belongs to the ABC
family of heterodimeric transmembrane
transporters, which are fueled by ATP
hydrolysis. TAP is localized in the mem-
brane of the ER and shuttles peptides
of variable length (
n
=
6t
o3
0am
i
n
o
acids)
from
the
cytosol
into
the
ER
lumen (Fig. 5). This is a prerequisite
previous page 368 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 370 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off