T-cell receptor–Major Histocompatibility Complex class I–peptide complex (TCR-pMHC-I)

The T-cell receptor–Major Histocompatibility Complex class I–peptide (TCR-pMHC-I) complex is the fundamental molecular assembly through which the adaptive immune system recognizes intracellular antigens presented on the surface of target cells (Rossjohn et al., 2015, Nature Reviews Immunology). This complex is formed when an intracellular protein is degraded into short peptide fragments, which are then loaded onto MHC class I molecules and transported to the plasma membrane. In the context of oncology, these peptides are often derived from tumor-associated antigens, neoantigens, or cancer-testis antigens, allowing CD8+ T cells to identify malignant cells that would otherwise remain invisible to antibodies (Blankenstein et al., 2015, Nature Reviews Cancer). Modern immunotherapies, such as TCR-engineered T cells (TCR-T) and Immune Mobilizing Monoclonal TCRs Against Cancer (ImmTACs), are designed to bind specifically to these pMHC complexes to trigger potent anti-tumor responses (Nathan et al., 2021, NEJM). For example, Tebentafusp is a bispecific molecule that targets the gp100 peptide presented by HLA-A*02:01, redirecting T cells to kill uveal melanoma cells. While highly promising, targeting the TCR-pMHC-I complex requires precise HLA matching and carries the risk of severe off-target toxicity if the targeted peptide sequence mimics those found in vital healthy tissues (Linette et al., 2013, Blood).

Other names

pMHC complexPeptide-MHC complexAntigen-MHC complexTCR-pMHCT-cell receptor–antigen–MHC complexT-cell receptor–MHC class I–tumor peptide complex

Therapeutic agents (such as TCR-T cells or bispecific TCRs) specifically bind the peptide-MHC complex on the target cell, triggering T-cell activation, cytokine release, and directed cytotoxic lysis of the target cell (D'Angelo et al., 2018, Cancer Discovery).