MHC CLASS II MOLECULES ARE LOADED WITH EXOGENOUS PEPTIDES

Proposed routes of intracellular trafficking of MHC

molecules involved in antigen presentation

MHC class II molecule processing compartment

antigen

surface
expression

cell surface
endocytosis
MIIC vesicle

early
endosome

antigen
displaces
Ii from
MHC
molecule
5

antigen
processing
late endosome/ DM
liposome

transport
vesicle
4

class II storage
vesicle

class I

class II
trans-Golgi
network

trans
Golgi
medial apparatus
cis
cytoplasmic
antigen
ribosomes

Fig. 7.12 Electron micrograph of ultrathin cryosections from B

cells showing a multilaminar MIIC vesicle. The bar represents
100 nm. MHC class II molecules are revealed by antibodies
coupled to 10 nm gold particles and HLA-DM by large gold
particles (15 nm). (Courtesy of Dr Monique Kleijmeer)

ER

nucleus

Fig. 7.11 Newly synthesized MHC class I molecules are loaded

with peptide (1). MHC class II molecules associate with Ii in
the ER (2). Ii prevents loading with peptide and contains
sequences that enable the MHC class II molecule to exit from
the rough endoplasmic reticulum (RER). MHC class I and class
II molecules segregate after transit through the Golgi (3). Class
I molecules go directly to the cell surface (4). Class II
molecules enter an acidic compartment called MIIC, where
they are loaded with peptide derived from exogenous antigen,
and the CLIP peptide that occupies the binding groove
dissociates (5).

MHC class I molecules in the ER, in a TAP-dependent

manner.
The exchange of CLIP for other peptides is orchestrated
by a class II-related molecule called HLA-DM (Fig. 7.13).
This glycoprotein consists of an chain and a chain,
both of which are encoded in the class II region of the
MHC (see Fig. 7.8).
HLA-DM acts by stabilizing empty MHC class II
molecules so that when CLIP is released other peptides
get a chance to associate. The DM molecule itself has a
closed groove and it is not capable of binding peptide.
In cell lines lacking DMA and DMB genes, class II
molecules are unstable and the cells no longer process and
present proteins. Their class II molecules end up at the
cell surface occupied by CLIP fragments of the invariant
chain (Fig. 7.14).

HLA-DM acts like a catalyst to influence binding of peptides in exchange for CLIP
peptide
Ii

CLIP

class II

class II

CLIP
peptide

DM

class II

DM

Fig. 7.13 An MHC class II molecule is

shown loaded with the Ii chain. The Ii chain
is cleaved to the CLIP fragment. Association
of the complex with HLA-DM then allows
CLIP to be exchanged for other peptides
derived from endocytosed proteins present
in MIIC vesicles.

class II

recycled

153