Structure and Functions of Major Histocompatibility Complex I

• MHC is a group of genes that encode proteins that allow the host to differentiate between self and non-self.
• Histocompatibility is derived from the Greek word for tissue (histo) and compatibility (compatibility).
• The human MHC resides on chromosome 6 and is known as the human leukocyte antigen (HLA) complex.
• HLA proteins fall into three distinct classes: Class I molecules are located on all nucleated cell types, but class II molecules are restricted to cells that can process antigens and transmit them to T lymphocytes.
• As we will see, macrophages, dendritic cells (DCs), and B cells are capable of antigen presentation in this manner.
• Finally, class III molecules include numerous immune-functioning proteins that are secreted. Class III molecules are not necessary for self-versus-non-self discrimination.

Class I MHC (Major Histocompatibility Complex) molecules

• Class I MHC molecules consist of HLA types A, B, and C and recognise as “self” every nucleated cell in the body.
• They are a combination of two protein chains, an alpha chain (45,000 Da) and 2-microglobulin (12,000 Da).
• Figure 33.3a demonstrates that only the alpha chain spans the plasma membrane. Each chain interacts with the other to generate a pocket that protrudes from the cell surface.
• This pocket can bind either self antigen, thereby identifying the cell as a host cell, or a peptide derived from an intracellular pathogen, thereby alerting the immune system that the cell is infected.
• HLA proteins vary between individuals; the greater the relationship between two persons, the more similar their HLA molecules.
• This is because each HLA gene exists in several forms (i.e., HLA genes are polymorphic). Multiple alleles of each gene have emerged via gene mutation, recombination, and other mechanisms over the course of evolution.
• Variation across people is magnified because HLA genes are codominant; hence, each individual expresses alleles from both parents at each A, B, and C locus. Consequently, an individual produces six distinct class I MHC proteins.
• As MHC class I proteins are present on all nucleated cells (only red blood cells lack them), they stimulate an immunological response when cells from one host with distinct class I molecules are transferred into another host with different class I molecules.
• This is the foundation for tissue type when preparing a patient for an organ or bone marrow transplant.

Cellular Distribution of Major Histocompatibility Complex I (MHC I)

• The majority of nucleated cells express the classical class I MHC molecules, however the level of expression differs amongst cell types.
• Class I molecules are most abundant in lymphocytes, where they make up around 1% of all plasma membrane proteins, or 5×105 molecules per cell.
• Comparatively, fibroblasts, muscle cells, liver hepatocytes, and brain cells express low numbers of class I MHC molecules.
• By limiting the possibility of graft detection by the recipient’s Tc, the low quantity on liver cells may contribute to the high success rate of liver transplants.
• A few cell types (such as neurons and sperm cells at particular periods of development) appear to be completely devoid of class I MHC molecules.
• As previously mentioned, a single MHC molecule can bind several peptides. Due to the codominant expression of the MHC alleles, a heterozygous individual expresses the gene products at each MHC locus that are encoded by both alleles.
• On each nucleated cell of an F1 mouse, the K, D, and L from each parent are expressed (six distinct class I MHC molecules).
• A heterozygous human expresses the A, B, and C alleles from each parent (six different class I MHC molecules) on the membrane of each nucleated cell.
• Each cell can present a large number of peptides in the peptide-binding clefts of its MHC molecules as a result of the creation of so many class I MHC molecules.
• Class I molecules will exhibit self-peptides in normal, healthy cells due to the natural turnover of self proteins. Both viral peptides and selfpeptides will be expressed in infected cells.
• On the membrane of a single virus-infected cell, many class I molecules displaying a variety of viral peptides are present.
• Due to allelic variations in the peptide-binding clefts of class I MHC molecules, diverse sets of viral peptides might be bound by different people within a species.

Major Histocompatibility Complex I (MHC I) Structure

The majority of nucleated cells have an assortment of MHC class I proteins. The peptides bound by these MHC class I molecules are typically endogenous, or derived from the breakdown of intracellularly produced proteins. The vast majority of these peptides will be “self” because the majority of proteins normally synthesised within a cell are of host origin at any given moment (as opposed to proteins of non-self origin, such as those generated during a viral infection). The MHC class I molecule does not distinguish between “self” and “non-self” peptides; CD8+ T cell TCRs provide this function. Due to the formation of central tolerance, self peptide–MHC complexes do not elicit an immunological response because T cells with the relevant specificity are often absent from the T cell repertoire. In contrast, non-self peptides complexed with MHC class I are identified and activate CD8+ T cells.

a. MHC Class I Component Polypeptides

• MHC class I α chains in both mice and humans are approximately 44 kDa glycoproteins with three extracellular globular domains.
• N-terminal domains α1 and α2 pair non-covalently to create the peptide-binding site, whereas the Ig-like α3 domain connects non-covalently with the β2m polypeptide.
• The α chain is also responsible for the transmembrane and cytoplasmic domains. The α1 domain maintains its shape without an internal disulfide bond, whereas the α2 an α3 domains include disulfide bonds.
• The β2m protein, the other partner of the MHC class I molecule, is a non-transmembrane polypeptide of around 12 kDa.
• β2m resembles a single Ig-like domain and, through its interaction with the MHC class I α3 domain, aids in the maintenance of the MHC class I molecule’s overall conformation.
• Indeed, the transport of the full heterodimer to the cell surface is dependent on the binding of β2m to the MHC class I α chain shortly after protein synthesis in the ER.

b. MHC Class I Peptide-Binding Site

• The MHC class I peptide-binding groove is relatively tiny. As a result, MHC molecules cannot detect big native antigens.
• Before antigens can be given to T cells, they must be digested into tiny peptides that can fit into the MHC groove.
• It is anticipated that each MHC class I molecule can attach to several hundred distinct peptides with reasonably high affinity, but can only capture one peptide at a time.
• The groove for binding class I MHC peptides is produced by the juxtaposition and contact of the α1 and α2 domains of the chain.
• The β2m chain helps by interacting with the amino acids that form the groove’s floor in α1 and α2.
• When the groove is occupied by a peptide consisting of 8–10 amino acids, these contacts are reinforced and the MHC class I structure is stabilised.
• Interactions between certain amino acids of the α1 and α2 domains and conserved “anchor residues” at the N- and C-termini of the peptide maintain its position in the groove.
• The peptide anchor residues point “down” into the groove, whereas the central residues point “up” toward the TCR.
• There is a considerable amount of conformational flexibility for peptides with widely diverse amino acid sequences to occupy the groove in the region between the anchor residues.
• Because the ends of the MHC class I groove are closed, peptides larger than 8–10 amino acids can only fit if their central residues bulge out of the groove.

How are self and non-self peptides deposited in the Major Histocompatibility Complex I (MHC I) binding pocket?

• Recall that proteasomes breakdown intracellular proteins as part of the natural process by which a cell recycles its protein content.
• Specific self and antigenic non-self peptides are transferred from the cytoplasm to the endoplasmic reticulum during this process (ER).
• The alpha chain of class I MHC and β2-microglobulin interact within the ER lumen. Attachment is restricted to peptides that fit properly into the binding cleft of one of the six distinct MHC I molecules.
• This process, known as endogenous antigen processing, allows the host cell to present peptide antigen to CD8+, or cytotoxic T lymphocytes, a subset of T cells (CTLs).
• Antigen-presenting CD8+ T lymphocytes express a receptor specific for class I MHC molecules. T lymphocytes “ignore” self-antigen presented by the host cell via MHC I molecules.
• T cells bind and destroy the host cell if the MHC class I molecule presents a non-self antigen (e.g., from an intracellular pathogen or a novel peptide found only in malignant cells).

Functions of Major Histocompatibility Complex I

Antigen Processing and Presentation

• Peptides are typically seen in nucleated cells, primarily self-peptides produced by protein turnover and faulty ribosomal products.
• During viral infection, infection by intracellular microorganisms, or transformation into cancer, these proteasome-degraded proteins are also loaded onto MHC class I molecules and displayed on the cell surface.

Transplant Rejection

• MHC molecules operate as antigens after transplantation of an organ or stem cells and can provoke an immunological response in the recipient, resulting in transplant rejection.
• Due to the considerable MHC variation in the human population and the fact that no two individuals, with the exception of identical twins, express identical MHC molecules, these molecules can facilitate transplant rejection.

References

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