Class I and Class II MHC antigens have a somewhat different structure.
MHC Class I molecules
- MHC Class I molecules in both human and mouse consist of two polypeptide chains that dramatically differ in size.
- The larger (α) chain has a molecular weight of 44 kDa in humans and 47 kDa in the mouse, and is encoded by an MHC Class I gene.
- The smaller chain, called β-2 microglobulin, has a molecular weight of 12 kDa in both species, and is encoded by a nonpolymorphic gene that is mapped outside of the MHC complex.
- There are no known differences in the structure of the human MHC Class I antigen a chains encoded by the HLA-A locus compared to those encoded by the HLA-B or the HLA-C loci, or in the structure of the murine MHC Class I antigen a chains encoded by the H-2K locus compared to those encoded by the H-2D or H-2L loci.
Regardless of which of these loci codes it, the a chain can be subdivided into the following regions, or domains:
- the peptide-binding domain;
- the immunoglobulin-like domain;
- the transmembrane domain; and
- the cytoplasmic domain.
- The peptide-binding domain is the most N-terminal; it is the only region of the molecule where allelic differences in the amino acid sequence can be localized.
- As seen from its name, the peptide-binding domain of the molecule includes the site to which antigenic peptides bind.
- It makes much sense to have this site exactly where the allelic differences are, because different MHC alleles accommodate peptides better or worse, thus influencing on the magnitude of the T-cell response.
- X-ray crystallography showed that the peptide-binding site in the MHC Class I molecules looks like a cleft that has a ‘‘floor’’ and two ‘‘walls’’ formed by spiral shaped portions of the alpha chain, called alpha 1 and alpha 2.
- Since the ‘‘floor’’ of the peptide-accommodating cleft is closed, only relatively small peptides, consisting of 9 to 11 amino acid residues, can be ‘‘stuffed’’ there.
- The immunoglobulin-like domain is structurally conserved, and resembles a domain of an antibody C-region.
- It contains the binding site for the T-cell accessory molecule CD8.
- The transmembrane and the cytoplasmic domains ensure that the alpha chain spans the membrane and is properly expressed by the cell.
- The β-2-microglobulin chain is also vitally important for the proper expression of the alpha chain.
- There are some mutant lymphoid cell lines (notably Daudi) that do not express MHC Class I molecules because of the defect in the β-2-microglobulin gene.
Class II MHC molecules
- Class II MHC molecules in both human and mouse consist of two polypeptide chains that have a similar, albeit not identical size.
- One of them is called alpha (α) and the other beta (β).
- The molecular weight of the a chain is 32–34 kDa, and of the b chain 29–32 kDa.
- A separate gene controls each of the chains.
- Thus, the murine I-A locus actually consists of the Iα and Iβ genes, the human HLA-DR locus of the HLA-DRα and HLA-DRβ, etc. Both the α and the β genes are polymorphic.
- The β genes of some of the MHC Class II loci can be tandemly duplicated, so, instead of one gene per homologous chromosome, a cell can have two or three.
- Because of that, one cell can simultaneously express more than two allelic products of each of the MHC Class II loci.
- For example, a cell can express allelic products of its HLA-DR molecule that can be identified as HLADRα1– HLA-DRβ1; HLA-DRα2 – HLA-DRβ2; HLA-DRα1 – HLA-DRβ2; HLA-DRα2 – HLA-DRβ1; etc.
- Overall, one cell can simultaneously express as many as 20 different MHC Class II gene products because of this tandem duplication phenomenon.
MHC Class I and Class II Molecules
- The structure of the a and the b chains of the MHC Class II molecules resembles that of the alpha chain of the MHC Class I molecules in that the former can be also divided into the peptide-binding, the immunoglobulin-like, the transmembrane and the cytoplasmic domains.
- One important difference, however, is that the peptide-binding cleft in Class II molecules is formed by both alpha and beta chains.
- Although positioned close to each other in space, the spirals of the alpha and the beta chains that form the cleft are not physically bound to each other.
- Because of that, the ‘‘floor’’ of the peptide-accommodating cleft in Class II MHC molecules is ‘‘open,’’ or ‘‘has a hole’’ in it.
- That allows MHC Class II molecules to accommodate peptides that are larger than those that fit MHC Class I molecules.
- The immunoglobulin-like domain of the MHC Class II molecules contains the binding site for a T-cell accessory molecule, CD4.
- This site cannot bind the above-mentioned CD8 molecule.