Peptide–Major Histocompatibility Complex class I (pMHC-I)

Peptide–Major Histocompatibility Complex class I (pMHC-I) complexes are essential cell surface structures that present intracellularly derived peptides to the adaptive immune system. These complexes are composed of an MHC class I heavy chain, a β2-microglobulin light chain, and a short peptide ligand, typically 8 to 12 amino acids in length, which is sampled from the cell's internal proteome. In malignant cells, pMHC-I complexes on the plasma membrane display fragments of tumor-associated antigens, neoantigens, or viral proteins, serving as specific markers for recognition by the T-cell receptors (TCRs) of CD8+ cytotoxic T cells. This recognition triggers a targeted immune response aimed at eliminating the abnormal cell. Modern immunotherapies, such as TCR-engineered T cells (TCR-T) and bispecific T-cell engagers (e.g., ImmTACs), specifically target these pMHC-I complexes to direct a potent immune attack against tumors, including those that lack traditional surface antigens. However, the clinical application of these therapies requires precise HLA matching and carries significant risks of off-target toxicity if the targeted peptide is shared with healthy tissues or if the engineered receptor cross-reacts with similar self-peptides.

Other names

HLA-peptide complexMHC-I-peptide complexTumor-associated antigen-MHC complexpHLA complexpMHC complexAntigen-MHC complex

T-cell redirection via bispecific T-cell engagers (ImmTACs), adoptive cell transfer of TCR-engineered T cells (TCR-T), and direct binding by TCR-mimic (TCRm) antibodies to induce cell-mediated cytotoxicity.