The Human Leukocyte Antigen (HLA) system, also known as the Major Histocompatibility Complex (MHC), is a complex group of genes on chromosome six. These genes encode proteins found on the surface of most cells that act as display racks for small protein fragments, or peptides. This display allows the immune system’s T-cells to check if a cell is healthy, infected, or abnormal. The HLA system is divided into two distinct groups, Class I and Class II, which perform surveillance roles using different molecular architectures and cellular locations.
Fundamental Structural Differences
The primary difference between the two classes is their molecular composition and the configuration of the peptide-binding groove. HLA Class I molecules are heterodimers composed of one long, transmembrane alpha (\(\alpha\)) chain and one smaller, non-MHC-encoded beta-2 microglobulin (\(\beta_2\)m) chain. The alpha chain is anchored to the cell membrane, and its \(\alpha_1\) and \(\alpha_2\) domains form the binding groove.
The Class I binding groove is closed at both ends, imposing a strict size limit. Consequently, Class I molecules primarily bind and present short peptides, typically eight to ten amino acids long. The closed nature of the groove ensures the peptide is precisely anchored within the molecule for T-cell recognition.
In contrast, HLA Class II molecules are composed of two roughly equal-sized transmembrane chains, an alpha (\(\alpha\)) chain and a beta (\(\beta\)) chain, both encoded within the MHC region. The peptide-binding groove is formed by the \(\alpha_1\) and \(\beta_1\) domains of the two chains.
The Class II binding groove is open at both ends, resembling an open pocket. This open topology allows Class II molecules to accommodate much longer peptides, generally ranging from twelve to twenty-five amino acids in length. The extended peptide hangs out of the groove, providing a distinct molecular signature compared to the shorter, contained peptides of Class I.
Cellular Distribution and Antigen Source
The cellular location of HLA molecules determines the origin of the antigens they present. HLA Class I molecules are expressed ubiquitously, found on the surface of virtually all nucleated cells in the body. This widespread distribution allows for constant immune surveillance.
The peptides displayed by Class I molecules are derived from the cell’s internal, or endogenous, environment. This includes fragments of normal cellular proteins and peptides from intracellular pathogens, such as viruses, or abnormal proteins from cancerous cells. Loading these internal peptides onto Class I is called the endogenous pathway.
HLA Class II molecules have a restricted cellular distribution, primarily found on specialized immune cells known as professional Antigen-Presenting Cells (APCs). These APCs include dendritic cells, macrophages, and B-cells.
The peptides presented by Class II molecules originate from the cell’s external, or exogenous, environment. APCs actively engulf material—such as bacteria or toxins—from outside the cell via phagocytosis. This engulfed material is broken down, and the resulting protein fragments are loaded onto Class II molecules for display, a mechanism referred to as the exogenous pathway.
Specific Immune Roles and T-Cell Interaction
The structural and locational differences determine the distinct roles of HLA classes in adaptive immunity and which type of T-cell they engage. HLA Class I molecules interact exclusively with CD8+ T-cells, known as Cytotoxic T Lymphocytes (CTLs). The CD8 protein on the T-cell acts as a co-receptor, binding to a specific domain (\(\alpha_3\)) on the Class I molecule to stabilize the interaction.
When a CD8+ T-cell recognizes a foreign peptide presented by Class I, it signifies the presenting cell is compromised, such as by viral infection or malignant transformation. The immune outcome of this recognition is the destruction of the presenting cell. This direct killing action is the basis of immune surveillance.
HLA Class II molecules interact exclusively with CD4+ T-cells, referred to as Helper T Lymphocytes. The CD4 co-receptor binds to the Class II molecule, ensuring a stable connection. Recognition of a foreign peptide on Class II signals that an external threat has been detected and processed by an APC.
The role of the CD4+ T-cell is to coordinate and amplify the overall immune response, not to kill the presenting APC. Upon activation, the helper T-cell releases signaling molecules called cytokines, which direct other immune cells. These cytokines can stimulate B-cells to begin producing antibodies or activate macrophages to increase their killing capabilities, orchestrating the broader immune defense.
HLA and Clinical Relevance
The polymorphism of the HLA system makes the distinction between Class I and Class II relevant in medical practice. The primary clinical application is in organ and bone marrow transplantation, where HLA typing minimizes the risk of transplant rejection. The immune system recognizes the donor’s HLA molecules as foreign.
Matching the donor and recipient at the HLA-A and HLA-B loci (Class I) and the HLA-DR locus (Class II) improves graft survival rates. A close match significantly reduces the likelihood of the recipient’s T-cells attacking the transplanted organ, a reaction known as alloreactivity.
Specific HLA alleles are associated with susceptibility to certain autoimmune diseases. The HLA-B27 allele (Class I) is linked to an increased risk of developing Ankylosing Spondylitis, a chronic inflammatory disease affecting the spine. In the Class II category, the HLA-DR4 allele is associated with Rheumatoid Arthritis, and specific HLA-DR and HLA-DQ combinations are risk factors for Type 1 Diabetes.