Major histocompatibility complex class I–peptide complex (pMHC-I)

Major histocompatibility complex class I–peptide complexes (pMHC-I) are heterotrimeric assemblies consisting of a polymorphic alpha heavy chain, a non-covalently associated beta-2 microglobulin (B2M) light chain, and a short antigenic peptide, typically 8 to 10 amino acids in length [PMID: 10688640]. Expressed on the surface of nearly all nucleated cells, these complexes function as molecular sensors that allow the immune system to monitor the internal proteome by presenting fragments of intracellular proteins to CD8+ cytotoxic T cells [PMID: 29425344]. In healthy cells, pMHC-I complexes present self-peptides to maintain immunological tolerance; however, in the presence of viral infection or malignant transformation, they present non-self or mutated neoantigen peptides that trigger T-cell activation and target cell lysis [PMID: 31434942]. Because they can present fragments from any intracellular protein, pMHC-I complexes are critical targets for modern immunotherapies, including TCR-engineered T cells (TCR-T) and bispecific TCR molecules like Tebentafusp, which can target intracellular antigens inaccessible to traditional antibodies [PMID: 34551229]. The primary challenges in targeting these complexes include the extreme polymorphism of the Human Leukocyte Antigen (HLA) system and the risk of lethal cross-reactivity if the targeted peptide sequence resembles one found in vital healthy tissues [PMID: 23945153].

Other names

HLA-peptide complexAntigen-MHC complexPeptide-MHC class I complexpMHCHuman leukocyte antigen class I–peptide complex

Presentation of intracellularly derived antigenic peptides to CD8+ T-cell receptors (TCRs) to initiate a cytotoxic immune response against infected or malignant cells.