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CHAPtER 5 The Major Histocompatibility Complex 83

to avoid immunosurveillance by flooding the local microenviron- dissociation of the CLIP peptide from the class II binding cleft
ment with soluble HLA-G and compromising the function of within the endosome, the relevant exogenous peptide is associated
immune cells. The expression of HLA-G in chorionic villi suggests with the class II molecule, as assisted by HLA-DM, prior to
a role in the maintenance of pregnancy. The mechanism appears transport of the stable HLA class II–peptide complex to the cell
to involve production of soluble forms of HLA-G. They appear surface.
to have an inhibitory role on the immune cells of the mother.
Uniquely among HLA molecules, HLA-G exists in different Nonclassic HLA-DM and HLA-DO
isoforms. Of these, four are expressed on the cell membrane, The nonpolymorphic nonclassic class II molecules HLA-DM
and three others exist as soluble forms. The functional significance and HLA-DO are exclusively expressed in endosomes, and they
of these isoforms is not known. regulate peptide binding to the classic HLA class II molecules.
HLA-DM, a peptide editor, plays a central role in peptide loading
Classic Class II HLA Molecules of MHC class II molecules. HLA-DO interacts with HLA-DM,
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Classic class II HLA molecules are selectively expressed in cells but its expression is more restricted.
of the immune system, similar to B cells, activated T cells,
macrophages, dendritic cells (DCs), and activated T cells. The Proteosome Elements Within the Class II Region
overall structure of class II HLA molecules is very similar to that The products of four genes in the class II region are involved
of class I HLA molecules. The HLA class II molecules are also with processing and loading peptides onto class I molecules
heterodimers that consist of two transmembrane glycoprotein (see Fig. 5.1). PSMB8 and PSMB9 are proteasome subunits
α (34 kDa) and β (29 kDa) chains. Unlike class I, however, both generating peptides from the breaking down of proteins.
the α and β chains are encoded by genes within the MHC. Each TAP1 and TAP2 transport the peptides from the cytoplasm to
of the two chains is composed of two extracellular domains. DR, the ER. The presence of these genes, which are related to the
DQ, or DP A1 include α 1 and α 2 domains that are encoded by functioning of HLA class I molecules, in the midst of genes
exons 2 and 3 of the gene. DR, DQ, or DP B1 include β 1 and β 2 encoding the HLA class II molecules, is probably the reason we
domains that are encoded by exons 2 and 3 of the gene. The α 1 observe strong LD within the MHC. It appears that allelic
and β 1 domains form the binding groove of the class II HLA forms of genes in the class I region require the presence of
molecule and are highly variable. The single exception is the α 1 allelic forms in the class II region, indicating functional inter-
domain of DR, which not polymorphic. The α 2 and β 2 domains dependencies developed throughout the evolutionary process
proximal to the membrane are members of the IgSF and have and therefore the need for being transmitted together from
limited polymorphisms (see Fig. 5.2). Unlike class I, where the generation to generation.
peptide-binding domain is encoded by α 1 and α 2 domains in
the same gene, trans-arrangement of α and β chains derived Principles of Peptide Presentation
from the two different haplotypes of the same or even different The mechanism by which HLA class I and class II molecules
isotypes permit combinatorial polymorphism in class II. present peptides became clear when the structures of these two
Although the structure of the peptide-binding cleft in class molecules were determined. A simplified diagram of the domain
II is homologous to that of class I, there are several distinct structure of MHC class I and class II proteins is depicted
differences that have major functional consequences. Among in Fig. 5.2. A more intricate ribbon structure of the actual class
the most important of these differences are those in length and I molecule interacting with the TCR is presented in Chapter 4.
cleft structure. The majority of peptides interacting with class For both class I and class II, the peptide-binding structure takes
II molecules have a length of >13 amino acids, whereas class I the shape of a β pleated floor with two α helix walls. The peptide
prefers peptides of nine amino acids. This is permitted in class lies within the groove created by these structures (see Fig. 5.3;
II because, unlike class I, the binding cleft is open at the ends Fig. 5.4).
and the ends of the peptide can extend on both sides of the HLA Each HLA molecule, whether class I or class II, binds a single
molecule. peptide; but the same HLA molecule has a significant degree of
The peptide is bound to the class II molecule through the promiscuity and can bind thousands of different peptides. Each
side chains of the peptide amino acids, which interact with five of the binding grooves is composed of individual polymorphic
different polymorphic pockets within the cleft. Loading of the pockets that dictate the binding of different peptides. Although
HLA class II molecules with peptides takes place primarily within the mode of TCR docking on HLA molecules is globally conserved,
the endosomes, where the HLA molecule interacts with endo- the shapes and chemical properties of the interacting surfaces
cytosed and phagocytosed extracellular antigens (Chapter 6). found in these complexes are so diverse that no fixed pattern of
To prevent binding of intracellular peptides in the class II pocket, contact has been recognized even between conserved TCR residues
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it first interacts with a protein called invariant chain (Ii) while and conserved side chains of the HLA α helices. Indeed, of the
the MHC molecule traffics through the endoplasmic reticulum amino acid side chains not bound to the HLA, only two or three
(ER). The invariant chain is a trimer, and each of its subunits are typically bound to the clonotypic TCR. This limited contact
binds noncovalently with an HLA class II molecule. The MHC– yields considerable TCR plasticity, which has the important
invariant chain complex also interacts with another chaperone evolutionary implication of freeing the HLA molecule and the
protein called calnexin. Upon release of calnexin, the class II peptide–HLA complex from the strict stereochemical constraints
molecule moves either directly into the late endosomal MHC that are usually imposed in receptor–ligand interactions. The
class II compartment (MIIC) or is cycled to the cell surface, consequence of TCR plasticity and this unusual receptor–ligand
where it is then internalized into the MIIC. Once in the endosomal interaction has been the evolutionary development of a uniquely
environment, invariant chain is degraded by proteases, including large number of different genes that encode various HLA
cathepsin S and L. It then leaves a fragment of peptide known structures, each of which is able to bind and present a different
as the class II–associated invariant chain peptide (CLIP). Upon range of peptides to the same clonotypic TCR.