How does MHC combine with antigenic peptides?

The major histocompatibility complex (MHC) refers to a group of closely linked genes encoding a histocompatibility antigen on a chromosome of a vertebrate, controlling intercellular immune recognition, and regulating immune responses. Among them, MHC of mice is called H-2 while human MHC is called Human Leukocyte Antigen (HLA).

Human MHC is located on chromosome 6 (6p21.31) and was first discovered on the surface of white blood cells, also known as Human Leukocyte Antigen (HLA). The HLA gene complex is located on the short arm of chromosome 6 6p21.31, with a total length of 3600 kb, a total of 224 gene loci, 128 functional genes, and 96 pseudogenes. From the side of the centromere, there are a class II gene, a class III gene, and a class I gene.

MHC binds to its product and presents antigenic peptides for recognition by TCR, which inevitably involves the binding of MHC molecules and antigenic peptides. The structure of the MHC class I and MHC class II molecule accepting the antigenic peptide is an antigen binding groove located at the distal end of the molecule. The difference is that the type I molecular groove is closed at both ends, and the accepted antigen peptide has a limited length of 8-10 amino acid residues; the type II molecular groove is open at both ends, and the length of the antigen peptide entering the groove varies greatly, from 13 to 17 amino acid residues, or even more.

Molecular basis of interaction between antigenic peptide and HLA molecule

The primary structure of various natural antigen peptides eluted from the HLA molecular antigen binding groove was analyzed, and it was found that there were two or more specific sites combined with the MHC molecular groove, which was called anchor positioning. The amino acid residue at this position is called an anchor residue. The lower panel is an antigenic peptide each of the two mouse MHC class I allele molecules, which are eight and nine amino acid residues in length. The octapeptide anchors are located at p5 (anchor residues Y and F) and p8 (anchor residues L); the nonapeptide anchors are located at p2 and p9. The anchor residues of p2 are Y, and the anchor residues of p9 is one of V, I, L. It follows that each of the two class I molecules receives an antigenic peptide, each having a specific consensus motif, x-x-x-x-Y/F-x-x-L and x-Y-x-x-x-x-x-x-V/I/L (x represents any amino acid residue).

The interaction between antigenic peptides and MHC molecules

A particular MHC molecule can selectively bind an antigenic peptide by virtue of the desired shared motif, in the sense that the combination of the two has a certain degree of specificity. It is thus inferred that different MHC allelic products may present different epitopes of the same antigen molecule, resulting in differences in the intensity of response of the same antigen to different individuals (with mutually different MHC alleles). This is actually an important mechanism by which MHC participates in and regulates immune responses with its polymorphism.

In-depth studies have found that MHC peptide (molecules) do not exhibit a strict one-to-one relationship with antigenic peptides, but a type of MHC molecule can recognize a group of peptides with specific common motifs, thereby constituting the flexibility of MHC molecules interacting with antigenic peptides.

This inclusiveness can be expressed at different levels:

First, the amino acid represented by 'x' in the common motif may be changed in order and structure;

Second, the anchor molecules of the same MHC molecule (especially class II molecules) required to be extracted into peptides often have more than one amino acid. As a result, the number of peptides that conform to a common motif can be quite large, resulting in a MHC molecules that may bind to multiple antigenic peptides and activate multiple antigen-specific T cell clones;

Third, antigenic peptides received by different MHC molecules may also have the same common motif.

For example, at least four families of A2, A3, B4, and B44 have been identified in HLA class I molecules, and members of these families can selectively recognize antigenic peptides possessing the same or similar anchor residues. This means that antigenic peptides that can be recognized and presented by a certain HLA molecule can also be presented by other molecules of the family. This facilitates the use of peptide vaccines or T cell vaccines for immunoprophylaxis and immunotherapy.

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