The Major Histocompatibility Complex (MHC) Class I is a key component of the body’s immune system, distinguishing between healthy “self” cells and compromised ones. This distinction is important for maintaining health and defending against internal threats. MHC Class I molecules communicate the internal state of nearly every cell to immune cells. Their ability to present cellular information is fundamental to initiating immune responses, ensuring the immune system identifies and addresses issues without harming healthy tissues.
Cellular Identity Markers
MHC Class I molecules are specialized protein complexes found on the surface of almost all nucleated cells and platelets in the body. Each molecule is a heterodimer, consisting of two different protein chains: a longer alpha (heavy) chain and a smaller, non-covalently associated beta-2 microglobulin (β2m) chain. The polymorphic alpha chain, encoded by HLA genes (HLA-A, HLA-B, HLA-C) on chromosome 6, has three extracellular domains (α1, α2, α3). The β2m subunit is not polymorphic and is encoded by a separate gene on chromosome 15.
The α1 and α2 domains of the heavy chain fold together to form a groove or cleft, which is the site where small protein fragments, or peptides, bind. This cleft accommodates peptides typically 8 to 10 amino acids in length. The α3 domain, which is highly conserved, interacts with the CD8 co-receptor on T cells. This structural arrangement allows MHC Class I molecules to display internal cellular proteins, signaling the cell’s identity and health status to the immune system.
Antigen Presentation and Immune Surveillance
MHC Class I molecules present internal cellular proteins, known as endogenous antigens, to the immune system. Cells continuously break down and recycle their proteins. During degradation, proteasomes generate small peptide fragments. These peptides are transported into the endoplasmic reticulum (ER) by Transporter Associated with Antigen Processing (TAP).
Within the ER, these peptides encounter newly synthesized MHC Class I molecules. A peptide-loading complex, including chaperone proteins, assists in the folding and stabilization of the MHC Class I molecule and its association with a suitable peptide. Peptides that bind tightly to the MHC Class I groove are retained, forming a stable complex. This peptide-MHC Class I complex is transported from the ER to the cell surface.
On the cell surface, these MHC Class I molecules, displaying their bound peptides, are inspected by cytotoxic T lymphocytes (CTLs), also known as CD8+ T cells. If a cell is infected by a virus or becomes cancerous, it produces abnormal or foreign proteins. Fragments of these abnormal proteins are processed and displayed on MHC Class I molecules alongside normal “self” peptides. When a CD8+ T cell recognizes a foreign or abnormal peptide presented by MHC Class I, it becomes activated and targets the compromised cell for destruction, eliminating the threat. This continuous process is fundamental to immune surveillance, ensuring the body remains free from harmful cells.
Role in Health and Disease
MHC Class I molecules are involved in maintaining health and various disease states. Their ability to present internal cellular peptides is significant in defense against viral infections. When a cell is infected by a virus, viral proteins are synthesized and processed into peptides, then presented on the cell surface by MHC Class I molecules. This allows CD8+ T cells to identify and eliminate infected cells, preventing viral replication and spread. Many viruses, however, have evolved mechanisms to interfere with MHC Class I presentation, evading immune detection.
MHC Class I also contributes to immune surveillance against cancer. Cancerous cells often produce abnormal or tumor-specific proteins, fragments of which can be displayed on MHC Class I molecules. CD8+ T cells can recognize these tumor antigens and destroy malignant cells, acting as a natural defense against tumor development. However, similar to viral evasion, many cancers can reduce or lose their MHC Class I expression or alter their antigen presentation machinery, allowing them to escape detection and elimination by T cells and progress.
Dysregulation of MHC Class I can contribute to autoimmune diseases, where the immune system mistakenly identifies healthy “self” cells as foreign and mounts an attack. Certain variations of HLA genes (MHC Class I in humans) are associated with an increased predisposition to specific autoimmune conditions, though exact mechanisms are still being researched. In these cases, the immune system’s ability to differentiate self from non-self becomes impaired, leading to chronic inflammation and tissue damage.
The polymorphic nature of MHC Class I molecules also has profound implications for organ transplantation. Because each individual expresses a unique set of HLA molecules, a mismatch between the donor’s and recipient’s MHC Class I types can lead to transplant rejection. The recipient’s immune system perceives the donor’s MHC Class I molecules as foreign antigens, triggering a strong immune response that attacks and destroys the transplanted organ. Therefore, tissue matching, particularly for HLA types, is a routine and important step before transplantation to minimize the risk of rejection and improve transplant success rates.