T-cell receptor-peptide-major histocompatibility complex (TCR-pMHC)

The T-cell receptor-peptide-major histocompatibility complex (TCR-pMHC) is the fundamental structural unit that enables T-cells to recognize specific antigens. This complex forms when a T-cell receptor (TCR) binds to a short peptide fragment nestled within the groove of a Major Histocompatibility Complex (MHC) molecule on the surface of a target cell (Murphy & Weaver, Janeway's Immunobiology, 2016). In oncology, this interaction is a primary target for TCR-engineered T-cell (TCR-T) therapies and Immune Mobilizing Monoclonal TCRs Against Cancer (ImmTACs), which are designed to recognize tumor-specific peptides presented by specific HLA alleles (Klaeger et al., Nature Chemical Biology, 2022). Unlike traditional antibodies that target surface proteins, TCR-based therapies can target the entire cellular proteome, including intracellular oncogenic drivers, by recognizing their processed peptides presented by MHC (Nathan et al., NEJM, 2021). Therapeutic examples include Tebentafusp, which targets the gp100 peptide/HLA-A*02:01 complex, and Afamitresgene autoleucel, which targets MAGE-A4 (FDA Label, 2022/2024). However, the clinical application is limited by the requirement for specific HLA matching and the risk of lethal cross-reactivity if the targeted peptide sequence is shared with proteins in healthy tissues (Linette et al., Blood, 2013).

Other names

TCR-MHC-antigen complexpMHC-TCR complexT-cell receptor-antigen-HLA complexPeptide-MHC-TCR interaction

T-cell redirection and activation through high-affinity binding to specific peptide-MHC complexes on target cells.