MHC class I molecule complexes lacking peptide areunstable, ensuring that only functionally useful complexesare available for interaction with TCRs.

A number of class I-like molecules canpresent very limited sets of antigens In addition to the standard MHC class I molecules (classIa), a number of class I-like molecules (class Ib), encodedin the MHC or elsewhere on the genome, can presentvery limited sets of antigens.

HLA-Esignal peptide complex interacts with theNKG2A inhibitory receptor on NK cells HLA-E molecules bind a restricted set of peptidesconsisting of hydrophobic leader sequence peptides fromclass Ia molecules. Intriguingly, though these leadersequences are generated by signal peptidase within theER, HLA-E is dependent on TAP transporters. Bybinding and presenting sequences from class Ia moleculesHLA-E signals the fact that MHC class Ia expression hasnot been downregulated (e.g. by a virus).

The HLA-Esignal peptide complex interacts with theNKG2A 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-Cmolecules be less well suited to the presentation of signalpeptide to receptors on NK cells than HLA-E?A. The conventional MHC molecules have evolved as highlydiverse molecules that present the great range of microbialpolypeptides to the diverse repertoire of T cell receptors. Incontrast HLA-E molecules have a single function to presentwell-defined signal peptides to a monomorphic receptor.

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

The location of antigen-processing genes inthe MHC may not be fortuitousThe finding of a cassette of antigen-processing genes suchas the LMPs and TAPs in the class II region of the MHCis striking.

There is some evidence, especially from studies in rats,that particular alleles of TAP are genetically linked withalleles of class I genes that are most suited to receive thekind of peptides preferentially transported by the productsof that TAP allele (Fig. 7.10).

The rat data suggest that localization of some antigen-processing genes in the MHC provides a selectiveadvantage. In fact, the clustering of antigen processing and presenting genes in the MHC of most vertebratespecies may not be fortuitous. It may help to coordinateco-evolution of some molecules as well as facilitatingexchange of sequences between loci.

MHC CLASS II MOLECULES ARE LOADEDWITH EXOGENOUS PEPTIDES MHC class II molecule and chains (see Chapter 5) arefound in the ER complexed to a polypeptide called theinvariant chain (Ii). This protein is encoded outside theMHC. The Ii complex is transported through theGolgi complex to an acidic endosomal or lysosomalcompartment called MIIC. These MIIC vesicles appear tobe specialized for the transport and loading of MHC classII molecules. They have characteristics of both endosomesand lysosomes and have an onion-skin appearance underthe electron microscope, comprising multiple membranestructures. The complex spends 13 hours in thiscompartment before reaching the cell surface. The Iichain is cleaved to small fragments, one of which, termedCLIP (class II-associated invariant peptide), is located inthe groove of the class II molecule until replaced bypeptides destined for presentation (Figs 7.11 and 7.12).

How do antigenic peptides derived fromexogenous proteins meet MHC molecules inthe appropriate compartment? The answer to this question lies in the intracellular trafficroutes of MHC molecules. After synthesis in the ER bothtypes of MHC molecule are transported through theGolgi compartment, class I in association with antigenicpeptide and class II bound to invariant chain Ii. Class IImolecules segregate from class I molecules in the trans-Golgi network. They then join the endosomal/lysosomalMIIC compartment en route to the plasma membrane.

Exogenous antigen can also enter APCs via anendocytic 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

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In rats, TAP genes are polymorphic and different allelesare linked in cis to the appropriate class I allele

Fig. 7.10 Different MHC class I molecules in rats canaccommodate peptides (blue bars) with either a positivecharge at the C terminus (+) or a neutral amino acid (o).Similarly, TAP molecules (orange) come in two forms, whichdiffer in the types of peptide they preferentially transport intothe ER. Most rat strains have the appropriate TAP allele on thesame haplotype as the class I gene that it serves best.

peptide chargedat C terminus

Ia Tapa

peptide neutralat C terminus

Ib Tapb