7.

ANTIGEN PRESENTATION

Absence of HLA-DM leads to failure of MHC class II

molecules to bind appropriate peptides
T cell activation
T cell

No T cell activation
T cell

TCR

CO-STIMULATORY MOLECULES ARE

ESSENTIAL FOR T CELL ACTIVATION

peptide
class
II

CLIP
DM

DM+ presenting cell

pathway into the cytosol where they are then subject to

processing and transport by proteasomes and TAP,
respectively, as for other peptides (Fig. 7.15).

class
II
DM cell

Fig. 7.14 In normal APCs (left) peptides are loaded onto class
II molecules, as shown in Fig. 7.13. In the absence of HLA-DM
(right), the CLIP fragment is not removed, and the blocked
MHC molecule is unable to activate T cells.

The process of activating T cells generally takes place

in the lymph node nearest to the infection. The TCR
recognizes a specific peptide lodged in the peptidebinding groove of the MHC molecule. This interaction
dictates immunological specificity because a peptide associated with an MHC molecule forms a unique structure to
be recognized by the TCR. Other molecules have a
complementary role in this interaction.
The initial encounter of T cells with APCs is by nonspecific binding through adhesion molecules. This
transient binding by adhesion molecules permits the
T cell to encounter a large number of different MHC
moleculepeptide combinations on different APCs. In the
absence of a specific interaction, the APC and T cell
rapidly dissociate.

Cross-presentation when exogenous peptides are

presented by MHC class I molecules

A further MHC-encoded molecule, HLA-DO (see

Fig. 7.8), which associates with DM, is also involved
in peptide loading. Like conventional MHC class II
molecules, HLA-DO is a heterodimer (see Chapter 5),
consisting of the DOA (formerly DNA) and DOB chains.
Similar genes and molecules to DM and DO are found in
other species, for example in mouse they are encoded by
the Ma, Mb, and Oa, Ob genes, respectively.

CTL

TCR
peptide
MHC class I

CROSS-PRESENTATION ALLOWS APCs TO

ACQUIRE ANTIGENS FROM INFECTED
CELLS

Cross-presentation occurs when exogenous peptides are

presented by MHC class I molecules. The principle that
endogenously synthesized proteins are the source of
peptides for MHC class I molecules appears to be violated
by the phenomenon of cross-presentation. There is a
specialized pathway in which T cells recognize MHC class
I moleculepeptide complexes formed from exogenous
protein antigens endocytically acquired by DCs.
Q. What function could cross-presentation fulfil in defense
against viral infections?
A. Presumably such a mechanism is required so that, even if a
virus fails to infect an APC directly, a successful cytotoxic CD8
T cell-mediated immune response can be generated.

In this process of cross-presentation, APCs acquire

remnants of virus-infected cells by phagocytosis and
present them on MHC class I molecules. Internalized
proteins appear to be transferred from the endocytic

154

MHC class II
processing

endocytosis

dendritic
cell

antigen

Fig. 7.15 DCs can present internalized antigen via both the
MHC class I and class II pathways. This is atypical external
antigen is usually presented via the class II pathway. Peptides
are transferred from the endosome to the cytosol where they
are processed by the proteasome to enter the class I pathway.