Peptides Assemble with Class Ii Mhc Molecules by Displacing CLIP

Recent experiments indicate that most class II MHC-invari-ant chain complexes are transported from the RER, where they are formed, through the Golgi complex and trans-Golgi network, and then through the endocytic pathway, moving from early endosomes to late endosomes, and finally to lyso-somes. As the proteolytic activity increases in each successive compartment, the invariant chain is gradually degraded. However, a short fragment of the invariant chain termed CLIP (for class II-associated invariant chain peptide) remains bound to the class II molecule after the invariant chain has been cleaved within the endosomal compartment. CLIP physically occupies the peptide-binding groove of the class II MHC molecule, presumably preventing any premature binding of antigenic peptide (see Figure 8-8).

A nonclassical class II MHC molecule called HLA-DM is required to catalyze the exchange of CLIP with antigenic peptides (Figure 8-10a). MHC class II genes encoding HLA-DM have been identified in the mouse and rabbit, indicating

Class Invariant II MHC chain

Digested invariant chain

-Released CLIP

CLIP 5 »-Peptides

"i HLA-DM

HLA-DO

Structure Hla
FIGURE 8-10

(a) Assembly of class II MHC molecules. Within the rough endoplasmic reticulum, a newly synthesized class II MHC molecule binds an invariant chain. The bound invariant chain prevents premature binding of peptides to the class II molecule and helps to direct the complex to endocytic compartments containing peptides derived from exogenous antigens. Digestion of the invariant chain leaves CLIP, a small fragment remaining in the binding groove of the class II MHC molecule. HLA-DM, a nonclassical MHC class II molecule expressed within endosomal compartments, mediates exchange of antigenic peptides for CLIP. The nonclassical class II molecule HLA-DO may act as a negative regulator of class II antigen processing by binding to HLA-DM and inhibiting its role in the dissociation of CLIP from class II molecules. (b) Comparison of three-dimensional structures showing the binding groove of HLA class II molecules (ai and pi) containing different antigenic peptides or CLIP. The red lines show DR4 complexed with collagen II peptide, yellow lines are DRi with influenza hemagglutinin peptide, and blue lines are DR3 associated with CLIP. (N indicates the amino terminus and C the carboxyl terminus of the peptides.) No major differences in the structures of the class II molecules or in the conformation of the bound peptides are seen. This comparison shows that CLIP binds the class II molecule in a manner identical to that of antigenic peptides. [Part (b) from Dessen et al., 1997, Immunity 7:473-481; courtesy of Don Wiley, Harvard University.]

that HLA-DM is widely conserved among mammalian species. Like other class II MHC molecules, HLA-DM is a heterodimer of a and ß chains. However, unlike other class II molecules, HLA-DM is not polymorphic and is not expressed at the cell membrane but is found predominantly within the endosomal compartment. The DMa and DMß genes are located near the TAP and LMP genes in the MHC complex of humans and DM is expressed in cells that express classical class II molecules.

The reaction between HLA-DM and the class II CLIP complex facilitating exchange of CLIP for another peptide is impaired in the presence of HLA-DO, which binds to HLA-DM and lessens the efficiency of the exchange reaction. HLA-DO, like HLA-DM, is a nonclassical and nonpolymorphic class II molecule that is also found in the MHC of other species. HLA-DO differs from HLA-DM in that it is expressed only by B cells and the thymus, and unlike other class II molecules, its expression is not induced by IFN-7. An additional difference is that the genes encoding the a and the ß chains of HLA-DO are not adjacent in the MHC as are all other class II a and ß pairs (see Fig 7-15).

An HLA-DR3 molecule associated with CLIP was isolated from a cell line that did not express HLA-DM and was therefore defective in antigen processing. Superimposing the structure of HLA-DR3-CLIP on another DR molecule bound to antigenic peptide reveals that CLIP binds to class II in the same stable manner as the antigenic peptide (Figure 8-10b). The discovery of this stable complex in a cell with defective HLA-DM supports the argument that HLA-DM is required for the replacement of CLIP.

Although it certainly modulates the activity of HLA-DM, the precise role of HLA-DO remains obscure. One possibility is that it acts in the selection of peptides bound to class II MHC molecules in B cells. DO occurs in complex with DM in these cells and this association continues in the endosomal compartments. Conditions of higher acidity weaken the association of DM/DO and increase the possibility of antigenic peptide binding despite the presence of DO. Such a pH-de-pendent interaction could lead to preferential selection of class II-bound peptides from lysosomal compartments in B cells as compared with other APCs.

As with class I MHC molecules, peptide binding is required to maintain the structure and stability of class II MHC molecules. Once a peptide has bound, the peptide-class II complex is transported to the plasma membrane, where the neutral pH appears to enable the complex to assume a compact, stable form. Peptide is bound so strongly in this compact form that it is difficult to replace a class II-bound peptide on the membrane with another peptide at physiologic conditions.

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  • azzeza
    Are mhc class ii cleaved?
    8 years ago

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