MHC class I and MHC class II molecules

Your immune system has an innate immune response which is immediate and nonspecific, as well as an adaptive immune response which is delayed and specific. The adaptive immune response is carried out by lots of unique B cells and T cells, which are highly specific for pathogens based on their unique parts - called antigens. Now, focusing on just T cells - they can only bind antigens, which are typically short peptides, when these antigens are displayed on a Major Histocompatibility Complex or MHC molecule, which is sort of like a silver platter that is on the surface of a cell.

The MHC molecules are also called human leukocyte antigens and these proteins are encoded for by MHC genes, which are found on chromosome 6. There are actually two groups of genes. One group of genes encodes the MHC class I molecule, which is bound by the CD8 molecule on the surface of cytotoxic T cells. Another group of genes encodes the MHC class II molecule, which is bound by the CD4 molecule on the surface of helper T cells. MHC class I genes encode the proteins HLA-A, HLA-B, and HLA-C, which is easy to remember as for MHC 1 it is always 1 letter. MHC class II genes encode the proteins HLA-DP, DQ, and DR which is also easy to remember because for MHC class 2 there are always 2 letters. And these genes are called histocompatibility because they are really important in determining whether or not a transplant is compatible or gets rejected. But their role isn’t just to wreak havoc on transplants! They’re critically important in making sure that different types of T cells recognize and react to antigens of microbes they are best designed to combat. And even though they’re called human leukocyte antigens, they’re not just found in leukocytes or white blood cells.

HLA proteins that code for MHC class I molecules are found on all nucleated cells throughout the body, even platelets which are fragments of nucleated cells! In fact, the only cells that don’t have them are mature erythrocytes which don’t have a nucleus. MHC class II molecules are only expressed on antigen presenting cells like monocytes, macrophages, dendritic cells, and B cells.

The MHC class I molecule has two protein chains, a larger alpha chain which contains both a peptide binding groove and a transmembrane region which anchors the MHC class I molecule onto the cell surface. And there’s a beta-2-microglobulin chain which is linked to the alpha chain. The alpha chain has three extracellular domains: alpha 1, alpha 2, and alpha 3. Alpha 1 and Alpha 2 make up the peptide binding groove. The beta-2-microglobulin basically props the whole structure up by binding between the alpha 1 & alpha 2 domains and the alpha 3 domain. The peptide binding groove of the MHC molecule binds peptides that are approximately 8-10 amino acids long and have many hydrophobic residues that will bind easily to the hydrophilic amino acids inside the groove.

MHC class I molecules allow immune cells to sample proteins from within your cells. To do this, MHC class I molecules use what’s called the endogenous pathway of antigen presentation. When a cellular protein is marked for degradation it’s sent to an organelle called the proteasome - which is found in all nucleated cells. The proteasome degrades the protein into short peptide chains, which are then transported to the endoplasmic reticulum using proteins called Transporters associated with Antigen Processing, or TAP for short. Meanwhile, the MHC class I molecule is being made with both the alpha chain and beta-2-microglobulin - and this is also happening in the endoplasmic reticulum. The TAP proteins load the short peptide chains onto the peptide groove of the MHC class I molecule using a molecule called Tapasin. The MHC class I and peptide then goes from the endoplasmic reticulum, through the golgi apparatus, and into an exocytic vesicle bound for the cell surface. Circulating cytotoxic T cells, as well as natural killer cells, which are innate immune cells that can directly kill target cells, can then interact with the MHC class I molecule and the antigen. If no recognition occurs, then the cell lives, but if these immune cells do recognize the peptide that’s being presented as foreign, then the cell gets attacked. The whole system is a bit like taking the trash and putting it on the corner each week. This allows the immune cells to investigate and know what’s going on within the cell on a regular basis, and can lead to early identification of a viral infection or abnormal protein synthesis in a cancerous cell.