The Major Histocompatibility Complex class I (MHC-I) molecule serves as a cellular surveillance system, monitoring the internal health of nearly every cell in the body. This system provides a constant display of a cell’s protein contents to patrolling immune cells. MHC-I molecules allow the immune system to distinguish between healthy, self-cells and those compromised by foreign invaders, such as viruses, or by internal malfunctions like cancer. This molecular display triggers the body’s targeted defense response against dangerous cells.
Molecular Structure and Cellular Location
The MHC-I molecule is a heterodimer composed of two different, non-covalently linked protein chains. The larger component is the polymorphic alpha (heavy) chain, which spans the cell membrane. The smaller, non-polymorphic component is the beta-2 microglobulin subunit. The alpha chain is folded into three distinct extracellular domains, with the alpha-1 and alpha-2 domains forming a deep groove. This specialized groove is the site where small protein fragments, or peptides, are securely bound and displayed on the cell surface.
MHC-I molecules are found on the surface of virtually all nucleated cells throughout the body, including platelets, but are notably absent on red blood cells. This widespread distribution ensures that every cell capable of being infected by an intracellular pathogen or becoming cancerous is under constant immunological scrutiny.
The Core Function: Signaling Internal Threats
The function of MHC-I is to display peptides derived from proteins synthesized within the cell, a process known as the endogenous pathway of antigen presentation. This begins when proteins inside the cell’s cytosol, whether normal self-proteins or foreign proteins from a virus, are marked for destruction. The cell’s recycling machinery, the proteasome, degrades these proteins into small peptide fragments, typically between eight and eleven amino acids long.
These newly generated peptides are transported from the cytosol into the endoplasmic reticulum (ER) by a specialized protein complex called the Transporter associated with Antigen Processing (TAP). Inside the ER, the peptides await newly synthesized MHC-I molecules that are being folded and stabilized with the help of chaperone proteins. Once a peptide binds to the MHC-I groove, the complex becomes stable and is released from the ER.
The fully assembled and peptide-loaded MHC-I molecule is then trafficked through the Golgi apparatus and inserted into the cell’s outer plasma membrane. This display is presented to patrolling immune cells, specifically the cytotoxic T lymphocytes (CTLs), which carry the CD8 co-receptor. If a CTL recognizes an MHC-I molecule presenting a foreign or aberrant peptide, such as one from a virus or a tumor, it triggers the destruction of the compromised cell.
Genetic Diversity and the HLA System
In humans, the genes that code for MHC molecules are located on chromosome six and are collectively known as the Human Leukocyte Antigen (HLA) system. The HLA genes are the most polymorphic genetic system known, with tens of thousands of different alleles currently identified in the population. This extreme diversity means that nearly every individual possesses a unique set of MHC-I molecules.
This extensive genetic variation results from evolutionary pressure, ensuring the species has a wide range of immune defenses against rapidly evolving pathogens. The practical consequence of this polymorphism is most evident in clinical settings, particularly in organ and stem cell transplantation. Successful transplantation requires a close match between the HLA types of the donor and the recipient to minimize the likelihood of the immune system recognizing the new organ as foreign and mounting a rejection response.
When MHC-I Fails: Immune Evasion
Viruses and cancer cells have evolved sophisticated mechanisms to interfere with the MHC-I system, allowing them to evade detection by cytotoxic T cells. A common strategy is to actively reduce the expression of MHC-I molecules on the cell surface, making the infected or cancerous cell invisible to surveillance. This downregulation can involve interfering with the proteasome, blocking the TAP transporter, or accelerating the degradation of the MHC-I molecule itself.
Reducing MHC-I expression, however, exposes the compromised cell to a different branch of the immune system: Natural Killer (NK) cells. NK cells operate under the “missing self” hypothesis, where they are inhibited by the presence of normal MHC-I molecules on a healthy cell. When a cell loses its MHC-I display, the inhibitory signal is removed, activating the NK cell to destroy the target.