MHC Class I, Class II, Antigen Processing, And Presentation


Major histocompatibility complex (MHC) is a group of genes that encode proteins that play a crucial role in the immune system. MHC proteins are divided into two main classes: MHC class I and MHC class II.

MHC class I molecules are one of the primary ways that the immune system recognizes and eliminates cells that are infected by viruses, bacteria, or other intracellular pathogens. They are also involved in tumor surveillance, transplantation rejection, and autoimmune diseases.

MHC class I molecules are expressed on the surface of almost all nucleated cells in the body, as well as platelets. They consist of two polypeptide chains: an alpha (α) chain and a beta-2-microglobulin (β2M) chain. The α chain is encoded by one of the three highly polymorphic genes: HLA-A, HLA-B, or HLA-C in humans. The β2M chain is encoded by a non-polymorphic gene on a different chromosome. The two chains are linked non-covalently by interactions between the α3 domain of the α chain and β2M.

The α chain of MHC class I molecules has three extracellular domains: α1, α2, and α3. The α1 and α2 domains form a peptide-binding groove that can accommodate peptides of 8 to 11 amino acids in length. These peptides are derived from the degradation of cytosolic proteins by the proteasome, a complex of proteolytic enzymes. The peptides are then transported from the cytosol to the endoplasmic reticulum (ER) by a transporter protein called TAP (transporter associated with antigen processing). In the ER, the peptides bind to newly synthesized MHC class I molecules with the help of chaperone proteins such as calnexin, calreticulin, tapasin, and ERp57. The peptide-MHC class I complex then exits the ER and travels to the cell surface via the Golgi apparatus.

The peptide-binding groove of MHC class I molecules is highly variable among different alleles, which allows them to present a diverse range of peptides to the immune system. The peptides bound by MHC class I molecules are recognized by cytotoxic T cells (CTLs), which express a receptor called TCR (T cell receptor) and a co-receptor called CD8. The TCR binds to the peptide-MHC class I complex, while CD8 binds to the α3 domain of the MHC class I molecule. This interaction triggers the activation and proliferation of CTLs, which then kill the target cell by releasing perforin and granzymes, or by inducing apoptosis through Fas-FasL interaction.

MHC class I molecules can also present peptides derived from exogenous antigens, such as those taken up by phagocytosis or endocytosis. This process is called cross-presentation and it allows the immune system to detect and eliminate cells that harbor extracellular pathogens or foreign particles. Cross-presentation can occur through different mechanisms, such as phagosome-to-cytosol transport, ER-phagosome fusion, or autophagy.

MHC class I molecules can also serve as ligands for natural killer (NK) cells, which are innate immune cells that can kill infected or abnormal cells without prior sensitization. NK cells express receptors that can either activate or inhibit their cytotoxic function depending on the presence or absence of MHC class I molecules on the target cell. Some of these receptors are called KIRs (killer cell immunoglobulin-like receptors) and they recognize specific alleles of HLA-A, HLA-B, or HLA-C. Other receptors are called NKG2A/C/E and they recognize HLA-E, which is a non-classical MHC class I molecule that presents peptides derived from other MHC class I molecules. NK cells use a balance between activating and inhibitory signals to determine whether to kill or spare a target cell.

In summary, MHC class I molecules are essential for presenting intracellular antigens to CTLs and for regulating NK cell activity. They are highly polymorphic and diverse, which enables them to cope with a variety of pathogens and foreign substances. They are also involved in many clinical scenarios, such as viral infections, cancer immunotherapy, organ transplantation, and autoimmune diseases.