The Major Histocompatibility Complex (MHC) is a group of genes that produce proteins found on the surface of nearly all cells in vertebrates. These proteins, known as MHC molecules, are fundamental to the adaptive immune system’s ability to distinguish between the body’s own cells and foreign invaders. By presenting small pieces of proteins, called peptides, the MHC molecules act as a communication system, initiating specific immune responses against detected threats. This system protects the body from infections and diseases.
MHC Class I: Presenting Internal Threats
MHC Class I molecules are composed of a heavy alpha chain with three external domains (α1, α2, α3), non-covalently associated with a smaller protein called beta-2 microglobulin (β2m). The α1 and α2 domains form a groove where peptides bind, while the α3 domain interacts with the CD8 co-receptor on T cells. These molecules are widely distributed, found on the surface of almost all nucleated cells in the body, including platelets, but not on red blood cells.
MHC Class I molecules primarily present “endogenous” antigens, peptides derived from proteins synthesized inside the cell. These proteins can originate from normal cellular processes, viral infections, or cancerous cells. When a cell is infected or cancerous, its internal proteins are broken down into small peptide fragments, typically 8-10 amino acids in length, by a cellular machinery called the proteasome. These fragments are then transported into the endoplasmic reticulum (ER) and loaded onto newly synthesized MHC Class I molecules.
Once loaded, the MHC Class I-peptide complexes travel to the cell surface, signaling internal cellular problems. The displayed peptides are then recognized by CD8+ cytotoxic T cells. If a CD8+ T cell recognizes a foreign peptide, it triggers an immediate immune response to eliminate the infected or abnormal cell, preventing disease spread.
MHC Class II: Alerting to External Invaders
MHC Class II molecules consist of two distinct polypeptide chains, an alpha (α) chain and a beta (β) chain, both of similar size. Each chain has two external domains, with the α1 and β1 domains forming the peptide-binding groove. This groove is open at both ends, allowing it to bind longer peptides, typically ranging from 13 to 25 amino acids in length.
Unlike MHC Class I, MHC Class II molecules are primarily found on specialized immune cells known as professional antigen-presenting cells (APCs). These include macrophages, dendritic cells, and B cells. APCs engulf and process “exogenous” antigens, peptides derived from proteins taken in from outside the cell, such as bacteria or other extracellular pathogens.
After an APC ingests an external pathogen, its proteins are broken down into peptide fragments within internal compartments like endosomes or phagosomes. Within these compartments, newly synthesized MHC Class II molecules, initially bound to a chaperone protein called the invariant chain, are loaded with these processed peptides. The invariant chain is removed to allow peptide binding. The MHC Class II-peptide complexes then move to the cell surface.
At the cell surface, these complexes alert the immune system to external threats by interacting with CD4+ helper T cells. CD4+ helper T cells recognize the presented peptides and become activated, orchestrating immune responses. This activation can lead to the stimulation of other immune cells, such as B cells to produce antibodies, and even assist in optimizing CD8+ T cell responses.
Distinguishing Their Roles in Immunity
The distinct structures and cellular distributions of MHC Class I and MHC Class II molecules directly reflect their specialized roles in the immune system. MHC Class I molecules are found on nearly all nucleated cells and present peptides derived from internal cellular proteins, such as those from viruses or cancer. These peptides are typically 8-10 amino acids long and are presented to CD8+ cytotoxic T cells, leading to the elimination of infected or abnormal cells.
In contrast, MHC Class II molecules are primarily found on professional antigen-presenting cells (APCs) like macrophages, dendritic cells, and B cells. They present peptides derived from external pathogens, such as bacteria, which are ingested by the APCs. These peptides are generally longer, ranging from 13-25 amino acids, and are presented to CD4+ helper T cells. This interaction activates helper T cells, which then orchestrate broader immune responses, including antibody production and the coordination of other immune cell activities.
Why These Differences Matter for Health
Understanding the distinct roles of MHC Class I and Class II molecules has significant implications for human health. Variations in human MHC genes, known as Human Leukocyte Antigens (HLAs), are linked to an individual’s susceptibility or resistance to certain autoimmune conditions. For example, specific HLA alleles, such as HLA-B27:05, are strongly associated with autoimmune diseases like ankylosing spondylitis, where the immune system mistakenly targets the body’s own tissues. This suggests that how these HLA molecules present self-peptides can influence whether an autoimmune reaction is triggered.
In the field of organ transplantation, HLA matching is a significant factor in preventing organ rejection. The immune system recognizes donor MHC molecules as foreign, leading to an immune attack on the transplanted organ if there are significant mismatches. Close HLA matching between donor and recipient is sought to minimize this immune response, often requiring immunosuppressive drugs to ensure transplant success.
The knowledge of antigen presentation pathways also guides the development of effective vaccines. By understanding how antigens are processed and presented by MHC Class I or Class II molecules, scientists can design vaccines that stimulate the appropriate T-cell responses, whether it’s a cytotoxic response against intracellular pathogens or a helper T-cell response for antibody production against extracellular threats. This targeted approach enhances vaccine efficacy.
Furthermore, manipulating MHC presentation is a strategy in cancer immunotherapy. Cancer cells can sometimes downregulate their MHC Class I expression to evade detection by the immune system. Researchers are exploring ways to enhance MHC presentation on tumor cells or to specifically target tumor-associated antigens presented by MHC molecules to boost the body’s natural defenses and eliminate cancerous cells.