366
Antigen Presenting Cells (APCs)
500 different peptides have been estimated
to constitute the self-peptide repertoire of
HLA-A2 expressed on the surface of a B
cell; however, none of these peptides binds
to HLA-A1 and vice versa. The reason is
that HLA-A1 and HLA-A2 differ strongly in
the anchor motif of their peptide ligands.
Today, more than 220 distinct HLA-A
and more than 450 distinct HLA-B type
alleles are known. Not all of the alleles have
distinct anchor motifs, however, the high
diversity of allelic MHC products observed
in the human population allows a high
diversity of self- and foreign peptides to be
bound. This strategy reduces the risk that
some pathogens may escape recognition
by the immune system due to holes in the
binding capacity of MHC molecules.
5.2
MHC Class II Molecules
The crystallographic structure of MHC
class II molecules shows that they are
folded
very
much
like
MHC
class
I
molecules, although class II dimers consist
of a noncovalent complex of an
α
-anda
β
-
chain, which are both encoded within the
MHC. Again, highly polymorphic regions
are located in the peptide-binding cleft,
consisting of 8
β
-strands and 2
α
-helical
segments that serve to sandwich peptide
ligands (Fig. 4).
The only and decisive structural differ-
ence is that the class II binding cleft is
open at both ends, whereas the class I
cleft is closed. A critical consequence is
that naturally processed peptides binding
to class II MHC molecules are at least 12
to 14 amino acids long and can be much
longer. The majority of class II–associated
peptides are 15- to 17-mers. The binding
forces of the class II peptide-binding cleft
are distributed to 3 to 4 speci±city pockets,
most often localized at relative positions
P1, P4, P6, and P9 (Table 4). Moreover,
aboutadozenhydrogenbondscontacting
the whole backbone of a typical 15-mer sta-
bilize the class II–peptide interaction. In
further contrast to class I molecules, the
speci±city pockets of the class II groove
are more permissive, often allowing 3 to 5
structurally similar amino acid side chains
to ±t into a particular pocket (Table 4).
The advantage of this peculiarity is that
class II molecules encoded by the same
MHC class II allele are able to accommo-
date a large repertoire of different peptide
sequences. This may be viewed as an adap-
tation to pathogens that constantly change
their immunodominant antigens by high
mutation rates. The disadvantage is that
MHC class II allele-speci±c peptide lig-
and motifs are rather complex and class
II–restricted immunodominant epitopes
are dif±cult to predict.
5.3
CD1 Molecules
CD1 molecules are nonpolymorphic trans-
membrane
glycoproteins
encoded
by
genes
outside
the
MHC.
The
overall
structure of CD1 is similar to that of
MHC class I molecules in that CD1
molecules form heterodimers of
45-kDa
heavy chains associated with
β
2m
.How
-
ever, unlike MHC class I molecules, CD1
is not retained within the endoplasmic
reticulum but is targeted at endocytic com-
partments where it binds its ligands. CD1
molecules are expressed only on dendritic
cells, monocytes, and some thymocytes.
Like classical MHC class I and class II
molecules, CD1 molecules are recognized
by T cells. However, unlike classical MHC
molecules, group I CD1 molecules (CD1a,
CD1b, CD1c), which are found in humans
but not in mice, present mycobacterial
lipids, mycolic acids, lipoarabinomannan,
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