MHCI

Major histocompatibility complex class I (MHCI) is a cell-surface protein complex encoded by MHC class I genes in vertebrates. It presents endogenously derived peptide antigens to CD8-positive cytotoxic T cells, enabling immune surveillance against infected or malignant cells.

MHCI molecules consist of a polymorphic heavy chain (alpha chain) with three extracellular domains α1, α2, α3, noncovalently associated with β2-microglobulin. The peptide-binding groove is formed by the α1 and α2 domains and typically binds peptides of about 8–10 amino acids with closed ends. The molecule is anchored in the cell membrane by a single transmembrane segment and a cytoplasmic tail.

Biogenesis: Intracellular proteins are degraded by the proteasome into peptides, which are transported to the endoplasmic reticulum by TAP1/TAP2. In the ER, MHCI heavy chain associates with β2-microglobulin and, with assistance from chaperones such as calnexin, calreticulin and ERp57, loads suitable peptides before trafficking via the Golgi to the cell surface.

Expression and genetics: MHCI is expressed on most nucleated cells, with low or absent expression on red blood cells. In humans, the three major loci HLA-A, HLA-B, and HLA-C are highly polymorphic, contributing to individual variation in antigen presentation.

Function and interactions: MHCI presents to CD8+ T cells through the T cell receptor and the CD8 co-receptor, triggering cytotoxic responses. Because many pathogens and tumors generate abnormal intracellular proteins, their peptides can be displayed. NK cells monitor MHCI levels; reduced expression can activate NK cells through missing-self recognition, providing a second layer of immune defense.

Clinical relevance: MHCI diversity is a key factor in transplant compatibility; dysregulation or mutations can contribute to autoimmunity, infectious disease susceptibility and cancer immunology research.