The immune system constantly monitors the body’s cells for trouble using the Major Histocompatibility Complex (MHC) Class I system. This system functions by taking protein fragments from within a cell and displaying them on the cell’s surface, providing a continuous “status report” to the immune system. This display mechanism allows the immune system to detect hidden threats. If a cell is infected with a virus, it produces viral proteins, and the MHC class I system presents fragments of these on its surface. Similarly, if a cell becomes cancerous, it produces abnormal proteins that are also displayed, marking the cell for destruction.
The Key Cellular Components
The MHC Class I pathway relies on several molecular players. The primary component is the MHC Class I molecule, a protein structure found on the surface of nearly all nucleated cells. This molecule is composed of a larger heavy chain and a smaller one called β2-microglobulin. The heavy chain folds to create a groove on the cell’s exterior, shaped to hold a peptide fragment of 8-10 amino acids.
Another component is the proteasome, the cell’s internal recycling and disposal system. This large protein complex in the cytoplasm is responsible for breaking down old, damaged, or unneeded proteins into smaller peptide fragments. This process ensures a constant supply of peptides that reflect the cell’s current protein makeup.
These generated peptides must then be moved into a specific cellular compartment. This transport is handled by the Transporter associated with Antigen Processing, or TAP. The TAP transporter is embedded in the membrane of the endoplasmic reticulum, where MHC Class I molecules are built. TAP acts as a gateway, pumping peptides from the cytoplasm into the endoplasmic reticulum, where they can be loaded onto MHC Class I molecules.
The Antigen Presentation Pathway
The journey of an antigen to the cell surface follows an organized pathway. It begins when proteins in the cytosol, which can be normal or foreign, are broken down by the proteasome into a pool of peptides. This step creates the raw material for the immune system’s inspection.
From the cytosol, these peptides must enter the endoplasmic reticulum (ER). This step is mediated by the TAP transporter, which moves peptides of the appropriate length and characteristics into the ER’s interior. This ensures that only suitable peptides are available for the next stage.
Inside the ER, new MHC Class I heavy chains and their associated β2-microglobulin partners are held by chaperone proteins, including calnexin and calreticulin. These chaperones help the MHC molecule fold correctly and position it near the TAP transporter, forming the peptide-loading complex. A peptide from the transported pool is then loaded into the binding groove of the MHC Class I molecule, which stabilizes the entire complex.
Once a peptide is securely bound, the MHC Class I molecule is released from the chaperone proteins. This stable MHC-peptide complex is then packaged into a vesicle. The vesicle travels from the endoplasmic reticulum, through the Golgi apparatus, and fuses with the outer cell membrane. This deposits the MHC-peptide complex onto the cell’s surface, ready for surveillance by the immune system.
T-Cell Recognition and Activation
With the MHC Class I complex displayed on the cell surface, specialized immune cells conduct surveillance. The primary inspector is the Cytotoxic T-cell, also referred to as a CD8+ T-cell. These cells patrol the body, examining the surfaces of other cells for signs of internal distress.
Recognition occurs when a Cytotoxic T-cell encounters a cell presenting an MHC-peptide complex. The T-cell uses its T-cell receptor (TCR) to scan these complexes. The TCR has a specific shape that allows it to bind only to a particular combination of MHC molecule and peptide. If the peptide is a normal self-peptide, the T-cell moves on, but if the TCR fits onto a foreign or abnormal peptide, it triggers a strong binding signal.
This binding activates the T-cell, transforming it into an effector cell that attacks the identified threat. It releases chemical agents, such as perforin and granzymes, from cytotoxic granules. Perforin creates pores in the target cell’s membrane, allowing granzymes to enter and trigger apoptosis, a controlled cellular suicide. This mechanism eliminates the source of the infection or the cancerous cell.
How Pathogens and Cancer Evade Detection
Viruses and cancer cells have developed strategies to subvert the MHC Class I pathway and evade the immune system. Many viruses produce proteins designed to interfere with antigen presentation. For instance, some herpesviruses and adenoviruses produce proteins that block the TAP transporter, preventing viral peptides from reaching the endoplasmic reticulum. Without the viral cargo, the MHC molecules cannot signal the infection.
Other viruses target the MHC Class I molecules directly. The human immunodeficiency virus (HIV), for example, produces a protein called Nef that causes MHC Class I molecules to be removed from the surface of infected cells. Some viruses produce proteins that trap MHC molecules within the endoplasmic reticulum or reroute them for destruction. These tactics reduce the number of viral peptides presented on the cell surface, hiding the infected cell from Cytotoxic T-cells.
Cancer cells also exploit this system for survival. A common characteristic of aggressive tumors is the loss of MHC Class I molecules from their surface. This can happen through mutations in the genes that code for MHC proteins or other pathway components, like the TAP transporter. By ceasing to produce these molecules, cancer cells offer no information about their abnormal proteins, making them invisible to T-cells and allowing the tumor to grow.