Major Histocompatibility Complex (MHC) proteins are surface molecules found on most cells in the body. They are central to the immune system’s ability to distinguish between “self” and “non-self” components. These proteins function as display platforms, presenting small molecular fragments, known as antigens, to immune cells. This presentation is important for the immune system to identify and respond to threats like infections or abnormal cells, while tolerating healthy body tissues. Without these proteins, the body’s defense mechanisms would struggle to recognize invaders or attack healthy cells.
What Are MHC Proteins?
MHC proteins are cell surface molecules encoded by the Major Histocompatibility Complex. In humans, this genetic region is called the Human Leukocyte Antigen (HLA) system, located on chromosome 6. Found on cell membranes, they act as molecular billboards showcasing tiny protein pieces. Each MHC molecule displays a protein fragment, also called an epitope, derived from the cell’s own proteins or foreign invaders.
MHC molecules bind these protein fragments, or antigens, and bring them to the cell surface. This allows specialized immune cells, particularly T cells, to “see” what is inside the cell or on its surface. This continuous display helps the immune system monitor the health of cells and detect any abnormalities.
The Two Main Classes of MHC
MHC proteins are categorized into two main classes: MHC Class I and MHC Class II. Each has distinct distributions and functions in antigen presentation. MHC Class I molecules are found on the surface of nearly all nucleated cells in the body, which includes almost every cell except red blood cells. These molecules present fragments of proteins produced inside the cell, such as those from viruses infecting the cell or from abnormal proteins found in cancer cells.
MHC Class II molecules have a more restricted distribution, found primarily on professional antigen-presenting cells (APCs). These specialized immune cells include macrophages, dendritic cells, and B cells. MHC Class II proteins present antigens that originate from outside the cell, such as fragments of bacteria or other foreign substances that have been engulfed and processed by the APCs. This division of labor ensures that different types of threats are presented to the appropriate immune cells for an effective response.
How MHC Proteins Present Antigens
Antigen presentation by MHC proteins involves several steps within the cell before the antigen-MHC complex reaches the cell surface. For MHC Class I, proteins from the cell’s cytoplasm (e.g., viral or aberrant cellular proteins) are broken down into peptide fragments by the proteasome. These fragments are then transported into the endoplasmic reticulum, where they bind to newly synthesized MHC Class I molecules. The MHC Class I-peptide complex then moves through the cell’s secretory pathway and is ultimately displayed on the cell surface.
Once on the cell surface, the MHC Class I-peptide complex is recognized by CD8+ cytotoxic T cells. If the presented peptide is foreign, such as from a virus, the CD8+ T cell becomes activated and can then target and destroy the infected cell.
For MHC Class II, external antigens like bacteria are taken up by professional antigen-presenting cells through endocytosis. Inside the cell, these antigens are degraded into peptides within specialized compartments called endosomes or lysosomes. The resulting peptides then bind to MHC Class II molecules, which have been transported to these compartments. This MHC Class II-peptide complex is subsequently transported to the cell surface. CD4+ helper T cells recognize these MHC Class II-peptide complexes. Their activation leads to the coordination and regulation of other immune cells, like B cells, to mount a broader immune response, such as antibody production.
MHC’s Role in Health and Disease
MHC proteins play a role in various aspects of human health and disease. In organ transplantation, MHC compatibility is a major factor in determining whether a transplanted organ is accepted or rejected. Differences in MHC molecules between the donor and recipient can lead to the recipient’s immune cells recognizing the transplanted organ as “non-self,” triggering a strong immune response that attacks and damages the new tissue.
MHC proteins are also implicated in the development of autoimmune diseases. In these conditions, the immune system mistakenly identifies the body’s own healthy tissues as foreign, leading to an attack on “self” cells. Specific variations in MHC genes can increase an individual’s susceptibility to certain autoimmune disorders by influencing how self-peptides are presented to T cells, sometimes leading to the activation of autoreactive immune cells.
MHC also plays a role in cancer immunity. Cancer cells often express abnormal proteins, and MHC Class I molecules can present fragments of these proteins to cytotoxic T cells, potentially leading to the destruction of the tumor. However, some cancer cells can evade immune detection by reducing or altering their MHC Class I expression, making them less visible to T cells. This understanding has led to the development of immunotherapies that aim to enhance MHC presentation or overcome these evasion mechanisms to improve anti-cancer responses.