The major histocompatibility complex (MHC) is a tightly linked group of genes in vertebrates. MHC products play a critical role in intercellular recognition, helping to distinguish between self and non-self. In humans, MHC is located on chromosome 6 and is known as the human leukocyte antigen (HLA) complex. In mice, it is located on chromosome 17 and is referred to as the histocompatibility-2 complex or H-2 complex.
Genetic Polymorphism and Co-Dominant Expression of MHC Genes
MHC genes are highly polymorphic, meaning there are multiple alleles for each MHC gene within a population, a phenomenon known as genetic polymorphism. MHC genes also exhibit codominant expression, meaning proteins from both alleles of the MHC genes are expressed in each cell. As a result, each individual inherits two sets of MHC alleles, one from each parent, allowing for a broad variety of MHC molecules, which enhances immunity diversity.
Inheritance and Haplotypes
MHC genes are closely linked on the chromosome, which means they are usually inherited as a single unit, known as a haplotype, from each parent. Consequently, each individual has one haplotype from their mother and one from their father, resulting in a unique combination of MHC molecules. Due to the high polymorphism of MHC genes, individuals within a species have a diverse set of inherited MHC genes.
Categorization of MHC Genes
MHC genes are classified into three main classes:
- Class I MHC Genes
- Class II MHC Genes
- Class III MHC Genes
Each class performs specific functions in the immune response. Class I and class II MHC genes encode MHC proteins that present antigens to T cells. Class I MHC molecules present antigens to cytotoxic T cells, while class II MHC molecules present antigens to helper T cells.
Functions of MHC Classes
Class I and Class II MHC Genes
Class I and II MHC genes encode antigen-presenting MHC molecules essential for immune response. Not all genes in these classes present antigens; some MHC genes encode proteins that do not present peptide antigens to T cells. These are referred to as non-classical MHC genes.
Class III MHC Genes
Class III MHC genes do not play a role in antigen presentation. Instead, they encode proteins involved in immune responses, such as components of the complement system, proteins associated with inflammation, and heat shock proteins (HSPs). Unlike class I and II genes, class III MHC genes are not categorized as classical or non-classical.
Class I MHC Proteins
Class I MHC genes code for glycoproteins called class I MHC molecules, which are found on most nucleated cells. Each gene encodes a transmembrane glycoprotein, typically 43 kDa in mass, called the alpha (α) or heavy chain, with three extracellular domains: α1, α2, and α3. The α3 domain is conserved and contacts the CD8 glycoprotein associated with T-cells.
Class I MHC molecules are expressed on cell surfaces with β2-microglobulin (β2m), a small polypeptide of about 12 kDa coded on a different chromosome (chromosome 15 in humans). Without β2m, the molecule cannot be displayed on the cell membrane.
Class I MHC molecules are expressed on nearly all nucleated cells with variation in expression levels. Lymphocytes have high expression, while other cells, like fibroblasts and hepatocytes, have lower levels.
Class II MHC Proteins
Class II MHC genes encode α and β chains with molecular masses of approximately 35 kDa and 28 kDa, respectively. These transmembrane glycoproteins have Ig-like extracellular domains (α and β domains) and are members of the Ig superfamily. CD4, found on Th cells, binds to the invariant part of Class II MHC molecules.
Class II MHC molecules are primarily expressed on specialized antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells.
Antigen-Presenting Cells (APCs)
APCs are divided into professional (e.g., dendritic cells, macrophages, and B cells) and non-professional types (e.g., fibroblasts, thymic epithelial cells). Professional APCs vary by location, and some can migrate freely or remain fixed in tissues. Notably, dendritic cells are efficient APCs with high levels of Class II MHC molecules.
Class III MHC Proteins
Class III MHC genes encode proteins vital to immune responses, including components of the complement system (e.g., C2 and C4) and inflammatory response proteins. Class III MHC molecules do not participate in antigen presentation or share structural features with Class I and II molecules.
Feature of Class I MHC Molecules
Structure
Class I MHC molecules consist of a polymorphic domain forming a peptide-binding groove. They present peptides resulting from intracellular protein processing.
Constitutive Expression
Class I MHC molecules are ubiquitously expressed on almost all nucleated cells, with varying expression across cell types.
T Cell Co-receptor Binding Site
The Class I MHC molecule has a co-receptor binding site that binds to the CD8 co-receptor on cytotoxic T cells (Tc cells), enabling Tc cells to recognize and destroy infected or abnormal cells.
Peptide Antigen Presentation
Class I MHC molecules display peptide antigens on the cell surface for Tc cell recognition. These peptides are typically 8–10 amino acids long, assembled onto the MHC molecule within the endoplasmic reticulum, and transported to the cell surface.
Recognition of Antigens by T Cell Receptors (TCRs)
Cytotoxic T cells (Tc cells) and helper T cells (Th cells) recognize antigen-MHC complexes. Self-MHC restriction ensures that TCRs bind antigens presented by MHC molecules from an individual’s specific genetic background, distinguishing self from non-self molecules. This mechanism is essential for immune tolerance and preventing autoimmune reactions.
