The Major Histocompatibility Complex (MHC) serves as a surveillance system within the body, allowing the immune system to differentiate between the body’s own cells and foreign invaders. This system involves a group of genes on chromosome 6 that produce proteins displayed on cell surfaces. MHC Class I (MHC-I) molecules are a part of this complex, acting as identifiers that help the immune system recognize “self” and detect “non-self” elements.
What is MHC-I?
MHC-I molecules are protein structures found on the surface of nearly all nucleated cells in the human body. Most cells, excluding red blood cells, display these molecules.
Each MHC-I molecule has two main parts: a heavy chain with three domains (alpha 1, alpha 2, and alpha 3), and a smaller protein called beta-2 microglobulin (β2m). The heavy chain is embedded in the cell membrane, and beta-2 microglobulin associates with the alpha 3 domain. This arrangement forms a groove where small protein fragments can bind. Beta-2 microglobulin is important for stabilizing the heavy chain and enabling peptide binding and surface expression.
How MHC-I Functions
MHC-I molecules present small protein pieces, called peptides, that originate from inside the cell. Internal proteins are continuously broken down by proteasomes in the cell’s cytoplasm. The resulting peptide fragments are then transported into the endoplasmic reticulum (ER) by Transporter Associated with Antigen Processing (TAP) proteins. Within the ER, these peptides are loaded onto newly synthesized MHC-I molecules with the help of chaperones, which aid proper folding and assembly.
Once a peptide is bound, the MHC-I molecule becomes stable and moves through the Golgi apparatus to the cell surface. On the cell surface, these MHC-I molecules display the internal peptides to the immune system. This presentation is inspected by cytotoxic T lymphocytes, also known as CD8+ T cells or killer T cells. The CD8+ T cell’s receptor recognizes the peptide presented by the MHC-I molecule, allowing the immune system to monitor the internal state of individual cells.
Role in Immune Defense
The display of internal peptides by MHC-I molecules is a defense mechanism that allows the immune system to detect and respond to threats originating from within the body’s cells. For instance, when a cell is infected by a virus, it produces viral proteins. Fragments of these viral proteins are processed and presented on the cell surface by MHC-I molecules. Similarly, cancerous cells often produce abnormal proteins, which are also loaded onto MHC-I molecules and displayed.
When a cytotoxic T lymphocyte (CD8+ T cell) encounters a cell presenting a foreign (e.g., viral) or abnormal (e.g., cancerous) peptide via its MHC-I molecule, the T cell recognizes this as a sign of danger. This recognition triggers the cytotoxic T cell to initiate a response, signaling the compromised cell for destruction. The T cell releases cytotoxic molecules like perforin and granzymes, which induce programmed cell death in the target cell, eliminating the threat and preventing its spread. This continuous surveillance by MHC-I and cytotoxic T cells is a key aspect of the immune system’s protection against internal cellular threats.
MHC-I and Health Implications
The function of MHC-I molecules has broad implications for various health conditions, including organ transplantation and cancer treatment. In organ transplantation, MHC-I (and MHC-II) compatibility between donor and recipient is essential. If the donor’s MHC-I molecules differ significantly from the recipient’s, the recipient’s immune system will recognize them as foreign, leading to an immune attack and rejection of the transplanted organ. Immunosuppressive therapies are often necessary to prevent this rejection.
Some viruses have evolved strategies to evade immune detection by interfering with MHC-I presentation. Certain viral proteins can block peptide transport into the endoplasmic reticulum or prevent MHC-I assembly and surface expression, making the infected cell “invisible” to cytotoxic T cells. This viral evasion highlights the constant evolutionary arms race between pathogens and the host immune system.
Understanding MHC-I presentation is also transforming cancer immunotherapy. Many cancer cells try to escape immune surveillance by reducing or inactivating their MHC-I expression, making them less visible to cytotoxic T cells. However, new immunotherapies aim to enhance the immune system’s ability to recognize and destroy cancer cells by boosting MHC-I presentation or by activating T cells to overcome these evasion mechanisms. Approaches like checkpoint blockade rely on re-invigorating anti-tumor CD8 T cells, which depend on proper MHC-I presentation.
Dysregulation of MHC-I can also contribute to autoimmune conditions. In these diseases, the immune system mistakenly identifies healthy self-peptides presented by MHC-I as foreign, leading to an immune attack on the body’s own tissues. Research into T cell activation and function control is leading to new insights for treating autoimmune diseases.