7.

ANTIGEN PRESENTATION

MHC class I molecule complexes lacking peptide are

unstable, ensuring that only functionally useful complexes
are available for interaction with TCRs.

In rats, TAP genes are polymorphic and different alleles

are linked in cis to the appropriate class I allele
peptide charged
at C terminus

A number of class I-like molecules can

present very limited sets of antigens

In addition to the standard MHC class I molecules (class

Ia), a number of class I-like molecules (class Ib), encoded
in the MHC or elsewhere on the genome, can present
very limited sets of antigens.
HLA-Esignal peptide complex interacts with the
NKG2A inhibitory receptor on NK cells
HLA-E molecules bind a restricted set of peptides
consisting of hydrophobic leader sequence peptides from
class Ia molecules. Intriguingly, though these leader
sequences are generated by signal peptidase within the
ER, HLA-E is dependent on TAP transporters. By
binding and presenting sequences from class Ia molecules
HLA-E signals the fact that MHC class Ia expression has
not been downregulated (e.g. by a virus).
The HLA-Esignal peptide complex interacts with the
NKG2A inhibitory receptor on NK cells (see Fig. 10.4).
A cell that expresses HLA-E is therefore not killed by
NK cells.
Q. Why would conventional HLA-A, HLA-B, or HLA-C
molecules be less well suited to the presentation of signal
peptide to receptors on NK cells than HLA-E?
A. The conventional MHC molecules have evolved as highly
diverse molecules that present the great range of microbial
polypeptides to the diverse repertoire of T cell receptors. In
contrast HLA-E molecules have a single function to present
well-defined signal peptides to a monomorphic receptor.

CD1 molecules present lipids and glycolipids

CD1 molecules, encoded on chromosome 1, present lipids
and glycolipids. Humans have five CD1 genes and mice
have two. CD1b presents the bacterial lipid mycolic
acid to T cells with TCRs. Other CD1 molecules are
recognized by T cells.

The location of antigen-processing genes in

the MHC may not be fortuitous

The finding of a cassette of antigen-processing genes such

as the LMPs and TAPs in the class II region of the MHC
is striking.
There is some evidence, especially from studies in rats,
that particular alleles of TAP are genetically linked with
alleles of class I genes that are most suited to receive the
kind of peptides preferentially transported by the products
of that TAP allele (Fig. 7.10).
The rat data suggest that localization of some antigenprocessing genes in the MHC provides a selective
advantage. In fact, the clustering of antigen processing
and presenting genes in the MHC of most vertebrate
species may not be fortuitous. It may help to coordinate
co-evolution of some molecules as well as facilitating
exchange of sequences between loci.

152

Ia

Tapa

peptide neutral
at C terminus

Ib

Tapb

Fig. 7.10 Different MHC class I molecules in rats can

accommodate peptides (blue bars) with either a positive
charge at the C terminus (+) or a neutral amino acid (o).
Similarly, TAP molecules (orange) come in two forms, which
differ in the types of peptide they preferentially transport into
the ER. Most rat strains have the appropriate TAP allele on the
same haplotype as the class I gene that it serves best.

MHC CLASS II MOLECULES ARE LOADED

WITH EXOGENOUS PEPTIDES

MHC class II molecule and chains (see Chapter 5) are

found in the ER complexed to a polypeptide called the
invariant chain (Ii). This protein is encoded outside the
MHC. The Ii complex is transported through the
Golgi complex to an acidic endosomal or lysosomal
compartment called MIIC. These MIIC vesicles appear to
be specialized for the transport and loading of MHC class
II molecules. They have characteristics of both endosomes
and lysosomes and have an onion-skin appearance under
the electron microscope, comprising multiple membrane
structures. The complex spends 13 hours in this
compartment before reaching the cell surface. The Ii
chain is cleaved to small fragments, one of which, termed
CLIP (class II-associated invariant peptide), is located in
the groove of the class II molecule until replaced by
peptides destined for presentation (Figs 7.11 and 7.12).

How do antigenic peptides derived from

exogenous proteins meet MHC molecules in
the appropriate compartment?

The answer to this question lies in the intracellular traffic

routes of MHC molecules. After synthesis in the ER both
types of MHC molecule are transported through the
Golgi compartment, class I in association with antigenic
peptide and class II bound to invariant chain Ii. Class II
molecules segregate from class I molecules in the transGolgi network. They then join the endosomal/lysosomal
MIIC compartment en route to the plasma membrane.
Exogenous antigen can also enter APCs via an
endocytic route (either receptor mediated or fluid phase,
see Fig. 7.11) where in some cells, such as DCs, it can
load onto:
MHC class II molecules in MIIC vesicles; and