MHC class I and MHC class II molecules

Definitions & Key takeaways

MHC class I molecules are found on the surface of all nucleated cells in the body. These molecules present peptides from within the cell to the immune system, and play an important role in alerting the immune system about cells infected by viruses. On the other hand, MHC class II molecules are found only on antigen-presenting cells, such as macrophages, dendritic cells, and B cells. These molecules present peptides from extracellular pathogens to the immune system.

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Your immune system has an innate immune response, which is immediate and non-specific, as well as an adaptive immune response, which is delayed in 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 1 molecule, which is bound by the CD8 molecule on the surface of cytotoxic T cells.
Another group of genes encodes the MHC class 2 molecule, which is bound by the CD4 molecule on the surface of helper T cells.
MHC class one genes encode the proteins HLAA, HLAB, and HLAC, which is easy to remember, as for MHC1, it is always one letter.
MHC class 2 genes encode the proteins HLADP, DQ, and DR, which is also easy to remember because MHC class 2, there are always two 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 to just 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 1 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 2 molecules are only expressed on antigen presenting cells, like monocytes, macrophages, dendritic cells, and B cells.
The MHC class 1 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 one 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 and alpha 2 domains and the alpha 3 domain.
The peptide binding groove of the MHC molecule binds peptides that are approximately 8 to 10 amino acids long and have many hydrophobic residues that will bind easily to the hydrophilic amino acids inside the groove.
MHC class 1 molecules allow immune cells to sample proteins from within your cells. To do this, MHC class one 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 proteosome, which is found in all nucleated cells.
The proteosome degrades the protein into short peptide chains, which are then transported into the endoplasmic reticulum using proteins called transporters associated with antigen processing, or TAP for short.
Meanwhile, the MHC class one 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 into the peptide groove of the MHC class one molecule using a molecule called tapasin.
The MHC class one 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 one 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.
If MHC class 1 molecules are designed to present antigens from inside the cell, then MHC class 2 molecules are designed to present antigens from outside the cell.
These are cells that engulf and destroy pathogens, and then present antigens to CD4 positive T helper cells. The MHC class 2 molecule also has two chains, an alpha chain and a beta chain, and each chain has two domains.
Both chains penetrate the cell membrane and contribute to the binding of the antigen at their alpha 1 and beta 1 domains.
The MHC class 2 molecule has a groove that can bind much larger peptides, 14 to 20 amino acids long on average. MHC class 2 molecules use the exogenous pathway of antigen presentation.
The exogenous pathway starts when a pathogen or a protein is ingested by an antigen presenting cell and brought into a vesicle called the endosome.
Granules within the phagocyte fuse with the endosome, forming a phagosome or phagolysosome. These granules are filled with proteolytic and degrading enzymes which degrade the pathogen or the protein into many small peptides.
Meanwhile, the MHC class 2 molecule is synthesized in the endoplasmic reticulum with all the other host proteins, including MHC class 1.
Instead of acquiring its peptide from within the endoplasmic reticulum like the MHC class 1 molecule. The binding cleft or groove of the MHC class 2 molecule is filled temporarily with a molecule called the invariant chain.
The MHC class 2 molecule and invariant chain are then transported through the cell in a vesicle where the invariant chain is degraded.
The vesicle with the MHC class 2 molecule then fuses with the phagolysosome, and the peptide cleft is filled by one of the peptides in the phagolysosome.
This vesicle now contains the MHC class 2 molecule that's bound to the peptide antigen, and it's transported to the cell surface, where it can present to circulating helper T cells, which can go on to stimulate the immune response.
All right, so, to recap, the MHC molecules or HLA proteins are encoded by MHC genes. MHC class one molecules include HLAA, B, or C, which are present on all nucleated cells throughout the body.
They use the endogenous pathway to process intracellular antigens into proteosomes and present them to CD8 positive cytotoxic lymphocytes.
MHC class 2 molecules include HLADP, DQ, and DR, which are found on professional antigen presenting cells. They use the exogenous pathway to process extracellular antigens and vesicles and present them to CD4 helper T cells.