T-cell receptor–Major Histocompatibility Complex (TCR-MHC)

The T-cell receptor–Major Histocompatibility Complex (TCR-MHC) is the central molecular assembly governing adaptive immune recognition. It involves the binding of a T-cell receptor (TCR) on a T lymphocyte to a peptide fragment presented by a Major Histocompatibility Complex (MHC) molecule on an antigen-presenting or target cell (Rossjohn et al., 2015). This interaction triggers a signaling cascade through the associated CD3 complex, leading to T-cell activation, proliferation, and immune effector functions such as cytokine release or direct cytotoxicity. In oncology, this complex is a primary target for TCR-engineered T-cell (TCR-T) therapies and soluble TCR-bispecific molecules like tebentafusp, which redirect T cells to kill tumor cells presenting specific antigens (Nathan et al., 2021; D'Angelo et al., 2024). In the context of autoimmunity, such as Type 1 diabetes, drugs like teplizumab target the TCR-CD3 complex to modulate the immune response and preserve beta-cell function (Herold et al., 2019). Therapeutic development focusing on this complex requires precise HLA-typing of patients, as TCR recognition is MHC-restricted. While highly effective, targeting this complex carries risks of cytokine release syndrome and off-target toxicities if the target peptide is expressed in healthy tissues.

Other names

TCR-pMHC complexT-cell receptor-peptide-MHC complexTCR-antigen-MHC complexTCR-HLA complexImmunological synapse

Therapeutic agents targeting the TCR-MHC complex function by redirecting T-cell cytotoxicity toward specific tumor antigens via engineered receptors or bispecific adapters, or by modulating the TCR-CD3 signaling complex to suppress unwanted immune responses in autoimmunity and transplantation (Rossjohn et al., 2015; Nathan et al., 2021).