The body’s defense system uses molecular identification tags, managed by the Major Histocompatibility Complex (MHC), to distinguish between self and non-self. In humans, MHC is known as Human Leukocyte Antigen (HLA). MHC molecules function as molecular pedestals, displaying protein fragments—called peptides—on the cell surface. These displayed peptides inform the immune system about the cell’s internal state or external environment. MHC Class I and MHC Class II differ fundamentally in their structure, the source of the peptides they display, and the specific immune cells they engage.
Fundamental Differences in Molecular Architecture
The composition of MHC Class I and Class II molecules dictates their function and cellular distribution. MHC Class I is a heterodimer composed of a large alpha (\(\alpha\)) chain, encoded by HLA genes, and a smaller, non-MHC-encoded protein called beta-2 microglobulin (\(\beta2\)-microglobulin). The \(\alpha\) chain anchors in the cell membrane and forms the peptide-binding groove. This groove is closed at both ends, restricting it to accommodating short peptides, typically eight to ten amino acids long.
In contrast, the MHC Class II molecule consists of two roughly equal-sized chains, an alpha (\(\alpha\)) chain and a beta (\(\beta\)) chain, both encoded within the MHC region. Both chains contribute to forming the peptide-binding groove, which is open at both ends. This open structure allows Class II to bind significantly longer peptide fragments, generally ranging from 13 to 25 amino acids.
The presence of these molecules on different cells establishes their roles in immune surveillance. MHC Class I molecules are expressed on the surface of nearly all nucleated cells in the body. This widespread distribution allows the immune system to constantly monitor the health and integrity of almost every cell. This enables swift detection and elimination of internally compromised cells, such as those infected by a virus or those that have become cancerous.
MHC Class II expression is restricted primarily to specialized immune cells known as professional Antigen-Presenting Cells (APCs). These include dendritic cells, macrophages, and B cells, which are strategically positioned to encounter foreign material. Concentrating Class II molecules on these cells ensures that information about external threats is collected and processed by dedicated sentinels before a broader response is initiated.
Distinct Pathways for Antigen Presentation
The difference in molecular architecture links directly to the distinct pathways used by each class to acquire and load peptides, reflecting whether the threat is internal or external. The MHC Class I pathway, or endogenous/cytosolic pathway, monitors the cell’s internal environment for abnormality. Proteins synthesized within the cell, such as viral or tumor proteins, are tagged by the ubiquitin system. The proteasome, a multi-protein complex, then degrades these tagged proteins into small peptide fragments.
These peptides are transported into the endoplasmic reticulum (ER), the site of MHC Class I assembly, by the Transporter associated with Antigen Processing (TAP). Inside the ER lumen, the MHC Class I heavy chain and \(\beta2\)-microglobulin are folded and stabilized by chaperone proteins. The MHC Class I molecule associates with the TAP complex while awaiting an appropriately sized peptide. Upon binding, the stable trimeric complex (MHC Class I, \(\beta2\)-microglobulin, and the peptide) dissociates from chaperones. It is then transported via the Golgi apparatus to the cell surface for immune inspection.
In contrast, the MHC Class II pathway, known as the exogenous or vesicular pathway, processes material ingested from the cell’s external surroundings. Professional APCs engulf extracellular pathogens, such as bacteria or toxins, via endocytosis or phagocytosis. The engulfed material is contained within internal vesicles that progressively acidify and fuse with lysosomes. Powerful enzymes within the lysosomes degrade the external proteins into peptides.
Concurrently, MHC Class II molecules are synthesized in the ER, where the peptide-binding groove is immediately blocked by the Invariant Chain (Ii). This chain prevents endogenous peptides from prematurely loading, ensuring dedication to external antigens. The MHC Class II-Ii complex travels through the Golgi toward the endosomal compartments containing the degraded external antigens. Within the acidic endosome, proteases cleave the Invariant Chain, leaving the CLIP fragment (Class II-associated Invariant Chain Peptide) blocking the groove. The non-classical MHC molecule, HLA-DM, then catalyzes the exchange of CLIP for a stable peptide derived from the engulfed foreign material. The resulting MHC Class II-peptide complex is then transported to the cell surface.
Directing the Immune Response
The outcome of antigen presentation depends on the MHC class involved and the specific T-cell subset it engages. MHC Class I is the sole partner for the CD8+ T cell, also known as a Cytotoxic T Lymphocyte (CTL). The CTL specializes in eliminating compromised host cells. When a CD8+ T cell receptor recognizes a foreign peptide presented by MHC Class I, the T cell activates and triggers the death of the presenting cell. This action clears the body of cells infected by intracellular pathogens or those that have undergone malignant transformation. The CD8 co-receptor binds directly to a non-polymorphic region of the MHC Class I molecule, enhancing interaction stability and ensuring correct pairing.
Conversely, the MHC Class II molecule interacts exclusively with the CD4+ T cell, or Helper T Lymphocyte. When a CD4+ T cell recognizes a foreign peptide presented by MHC Class II on an APC, the Helper T cell activates but does not kill the presenting cell. The CD4+ T cell’s role is coordination and instruction for the broader immune response. The activated Helper T cell releases signaling molecules called cytokines, which act as chemical messengers to other immune cells. These signals coordinate the immune response, promoting B cells to produce antibodies or activating macrophages to enhance killing capabilities.