Peptide–MHC class I complex (pMHC-I)

The Peptide–MHC class I complex (pMHC-I) is a fundamental molecular assembly expressed on the surface of nearly all nucleated cells, serving as a critical interface between the intracellular environment and the adaptive immune system. It consists of a polymorphic MHC class I heavy chain (HLA-A, -B, or -C in humans), a non-polymorphic beta-2 microglobulin (β2m) light chain, and a short antigenic peptide, typically 8 to 10 amino acids in length, derived from the proteasomal degradation of cytosolic proteins. The primary biological function of pMHC-I is to present these peptides to CD8+ cytotoxic T lymphocytes (CTLs); recognition of a foreign or mutated peptide by a specific T-cell receptor (TCR) triggers an immune response that leads to the destruction of the presenting cell. In the context of disease, pMHC-I complexes display neoantigens in cancer or viral epitopes during infection, making them highly specific targets for precision immunotherapies. Current therapeutic modalities targeting pMHC-I include TCR-engineered T cells (TCR-T), bispecific T-cell engagers (e.g., ImmTACs), and TCR-like antibodies, which aim to selectively eliminate diseased cells while sparing healthy tissue. However, therapeutic efficacy can be challenged by tumor-mediated HLA downregulation and the risk of off-target toxicity due to cross-reactivity with similar self-peptides.

Other names

pMHC-IHLA-peptide complexMHC-I/peptide complexPeptide-HLA class I complexpMHCIAntigen-MHC class I complex

Direct binding of TCR-engineered cells or bispecific molecules to the specific peptide-HLA complex, leading to T-cell mediated lysis of the target cell; induction of ADCC by TCR-like antibodies.