ch 7 antibody 7e09

MHC class I molecules in the ER, in a TAP-dependentmanner.

The exchange of CLIP for other peptides is orchestratedby 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 theMHC (see Fig. 7.8).

HLA-DM acts by stabilizing empty MHC class IImolecules so that when CLIP is released other peptidesget a chance to associate. The DM molecule itself has aclosed groove and it is not capable of binding peptide.

In cell lines lacking DMA and DMB genes, class IImolecules are unstable and the cells no longer process andpresent proteins. Their class II molecules end up at thecell surface occupied by CLIP fragments of the invariantchain (Fig. 7.14).

MHC CLASS II MOLECULES ARE LOADED WITH EXOGENOUS PEPTIDES

153

Proposed routes of intracellular trafficking of MHCmolecules involved in antigen presentation

Fig. 7.11 Newly synthesized MHC class I molecules are loadedwith peptide (1). MHC class II molecules associate with Ii inthe ER (2). Ii prevents loading with peptide and containssequences that enable the MHC class II molecule to exit fromthe rough endoplasmic reticulum (RER). MHC class I and classII molecules segregate after transit through the Golgi (3). ClassI molecules go directly to the cell surface (4). Class IImolecules enter an acidic compartment called MIIC, wherethey are loaded with peptide derived from exogenous antigen,and the CLIP peptide that occupies the binding groovedissociates (5).

cell surfacesurface

expression

transportvesicle

antigenprocessing

antigendisplacesIi fromMHCmolecule

class II storagevesicle

trans-Golginetwork

trans

medial

cis

Golgiapparatus

cytoplasmicantigen

ribosomesER

antigen

3

21

4

5

nucleus

class I class II

DMlate endosome/liposome

MIIC vesicleearlyendosome

endocytosis

MHC class II molecule processing compartment

Fig. 7.12 Electron micrograph of ultrathin cryosections from Bcells showing a multilaminar MIIC vesicle. The bar represents100 nm. MHC class II molecules are revealed by antibodiescoupled to 10 nm gold particles and HLA-DM by large goldparticles (15 nm). (Courtesy of Dr Monique Kleijmeer)

N

HLA-DM acts like a catalyst to influence binding of peptides in exchange for CLIP Fig. 7.13 An MHC class II molecule isshown loaded with the Ii chain. The Ii chainis cleaved to the CLIP fragment. Associationof the complex with HLA-DM then allowsCLIP to be exchanged for other peptidesderived from endocytosed proteins presentin MIIC vesicles.

class II

Ii

class II DM DM

CLIP

class II class II

recycled

peptide

peptide

CLIP