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

The T-cell receptor-peptide-major histocompatibility complex (TCR-pMHC) is the fundamental molecular assembly that mediates the recognition of infected or malignant cells by the adaptive immune system (Bentzen & Hadrup, 2017). It consists of a T-cell receptor (TCR) on the surface of a T lymphocyte binding to a specific peptide antigen presented by a major histocompatibility complex (MHC) molecule on a target cell. During the in vivo effector phase, this interaction triggers the T-cell to perform its specialized functions, such as the release of cytotoxic granules or the production of effector cytokines like interferon-gamma (Murphy & Weaver, 2016). This complex is a critical therapeutic target because it allows for the recognition of intracellular antigens, which are otherwise inaccessible to conventional antibody-based therapies. Therapeutic interventions targeting this complex include TCR-engineered T-cell (TCR-T) therapies and soluble bispecific molecules like Immune Mobilizing Monoclonal TCRs Against Cancer (ImmTACs) (Nathan et al., 2022). For example, Tebentafusp is a bispecific protein that redirects T-cells to kill gp100-expressing melanoma cells by binding to the gp100 peptide-HLA-A*02:01 complex. Clinical success in this area depends heavily on the specificity of the TCR for the pMHC and the expression levels of the target antigen on diseased versus healthy tissues. Safety concerns primarily involve off-target cross-reactivity with similar self-peptides and systemic inflammatory responses like cytokine release syndrome (D'Angelo et al., 2018).

Other names

TCR-pMHC complexTCR-antigen-MHC complexPeptide-MHC-TCR complexpMHC-TCR interactionMHC-peptide-TCR complex

TCR-engineered T-cells (TCR-T) or soluble TCR-based bispecific molecules (ImmTACs) bind specifically to the peptide-MHC complex on the surface of target cells, facilitating direct T-cell mediated lysis and the release of effector cytokines.