Major Histocompatibility Complex (MHC) Class I molecules are components of the immune system, acting as a surveillance system. They help the immune system differentiate between healthy “self” cells and those that are infected or abnormal. By displaying internal cellular information, they enable continuous monitoring of cells, a process known as immune surveillance. This vigilance helps maintain overall health and protect against various threats.
Understanding MHC Class I
MHC Class I molecules are protein complexes found on the surface of nearly all nucleated cells, including platelets, but not red blood cells. In humans, they are also known as Human Leukocyte Antigens (HLA), with major subtypes including HLA-A, HLA-B, and HLA-C. Each MHC Class I molecule is a heterodimer, composed of two different polypeptide chains: a larger alpha (α) chain and a smaller beta-2 microglobulin (β2m) chain. The α chain is encoded by genes within the MHC region, while the β2m subunit is encoded by a separate gene.
The α chain has three extracellular domains (α1, α2, and α3), a transmembrane region that anchors the molecule to the cell surface, and a short cytoplasmic tail. The α1 and α2 domains form a groove where small protein fragments, called peptides, bind. The β2m chain associates non-covalently with the α chain, providing stability to the complex. This structural arrangement allows MHC Class I molecules to display a snapshot of the cell’s internal protein environment on its surface.
How MHC Class I Molecules Present Information
The primary function of MHC Class I molecules is to present peptides derived from proteins synthesized inside the cell. This process begins with the breakdown of intracellular proteins (normal, viral, or cancerous) into smaller peptide fragments. This degradation occurs through a cellular machinery called the proteasome. These short peptides (usually 8 to 11 amino acids) are then transported from the cytoplasm into the endoplasmic reticulum (ER) by the Transporter Associated with Antigen Processing (TAP).
Within the ER, newly synthesized MHC Class I molecules, associated with chaperone proteins like calnexin and tapasin, await peptide loading. Once a suitable peptide binds to the groove formed by the α1 and α2 domains, the complex becomes stable. This stable MHC Class I-peptide complex then moves through the Golgi apparatus to the cell surface. At the cell surface, the presented peptide is “inspected” by cytotoxic T lymphocytes (CTLs), also known as CD8+ T cells. The CD8 co-receptor on the T cell interacts with the α3 domain, stabilizing the interaction while the T cell receptor (TCR) on the CTL examines the presented peptide for foreignness.
The Role of MHC Class I in Immune Defense
MHC Class I molecules play a direct role in immune defense by continuously monitoring cells for internal abnormalities. Every nucleated cell constantly processes its own proteins, presenting fragments of these “self” proteins on its MHC Class I molecules. When a cell is infected by a virus, it produces viral proteins. Fragments of these viral proteins are then processed and displayed on the cell’s MHC Class I molecules alongside self-peptides. Similarly, if a cell undergoes cancerous transformation, it may produce abnormal or mutated proteins, which can also be presented on MHC Class I.
The presentation of these non-self or abnormal peptides acts as a signal to cytotoxic T lymphocytes (CTLs). When a CTL recognizes a foreign peptide presented by an MHC Class I molecule, it indicates the cell is compromised. This recognition triggers the activation of the CTL, leading to the elimination of the infected or cancerous cell. This targeted destruction prevents the spread of infection and removes abnormal cells, maintaining the body’s health and integrity. MHC Class I molecules also serve as ligands for inhibitory receptors on natural killer (NK) cells, preventing NK cells from attacking healthy cells that express self MHC Class I.
MHC Class I and Human Health
MHC Class I molecules have significant implications for human health. In organ transplantation, differences in MHC Class I molecules (HLA) between a donor and a recipient can lead to graft rejection. The recipient’s immune system may recognize the donor’s MHC Class I molecules as foreign, initiating an immune attack against the transplanted organ. Matching HLA types between donor and recipient is therefore a major consideration to improve transplant success rates.
Errors in MHC Class I presentation can also contribute to autoimmune diseases. In these conditions, the immune system mistakenly attacks healthy “self” cells. For example, specific HLA Class I alleles, such as HLA-B27, are correlated with conditions like ankylosing spondylitis, where the immune system targets its own tissues. Similarly, HLA-B51 is a significant risk factor for Behcet disease, and certain HLA-A, HLA-B, and HLA-Cw alleles are linked to psoriasis.
Understanding MHC Class I molecules has also advanced cancer immunotherapy. Cancer cells often evade immune detection by reducing or altering their MHC Class I expression to hide from cytotoxic T cells. Immunotherapy strategies aim to counteract this evasion by enhancing the visibility of cancer cells to the immune system. This can involve therapies that encourage cancer cells to express more MHC Class I molecules or make them more recognizable to T cells, enabling the immune system to fight cancer more effectively.