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

The T cell receptor–peptide–major histocompatibility complex (TCR-pMHC) is a fundamental supramolecular assembly that mediates the adaptive immune response by enabling T cells to recognize specific antigens. This complex is formed when a T cell receptor (TCR) binds to a peptide fragment presented by a major histocompatibility complex (MHC) molecule on the surface of an antigen-presenting cell or a target cell. The formation of this ternary complex, often stabilized by co-receptors like CD4 or CD8, triggers intracellular signaling through the CD3 complex, leading to T cell activation, proliferation, and the execution of effector functions such as the destruction of infected or malignant cells. In modern immunotherapy, the TCR-pMHC interaction is a critical therapeutic target, particularly for treating solid tumors where intracellular antigens are presented as pMHC epitopes. Drugs such as tebentafusp and afamitresgene autoleucel are designed to exploit this recognition mechanism to redirect the immune system against specific cancer cells. However, the therapeutic application is complicated by the risk of severe toxicities, including cytokine release syndrome and potential off-target cross-reactivity with similar self-peptides found in healthy tissues.

Other names

TCR-pMHC complexpMHC-TCR complexT-cell receptor–MHC-peptide complexTernary TCR-pMHC complexTCR-peptide-MHC complex

Drugs targeting the TCR-pMHC complex primarily act by redirecting T cell-mediated cytotoxicity toward cells presenting specific antigen-derived peptides. This is achieved either through engineered T cells expressing high-affinity TCRs (TCR-T) or bispecific molecules (ImmTACs) that bridge the pMHC on target cells with the CD3 complex on effector T cells, thereby bypassing natural immune tolerance and inducing targeted cell lysis and cytokine release.