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 at the immune synapse that enables T cells to recognize and respond to specific antigens (Dustin, M. L., 2014, Nature Reviews Immunology). This complex is formed when a T cell receptor (TCR) binds to a short peptide fragment derived from a protein antigen, which is held and presented by a major histocompatibility complex (MHC) molecule on the surface of an antigen-presenting cell or a target cell (Rossjohn, J., et al., 2015, Annu Rev Immunol). The specificity and affinity of the TCR–pMHC interaction are critical for discriminating between self and non-self, thereby governing immune homeostasis and the elimination of pathogens or malignant cells. In therapeutic contexts, this complex is targeted by TCR-engineered T cells (TCR-T) and bispecific molecules like Immune Mobilizing Monoclonal TCRs Against Cancer (ImmTACs), such as Tebentafusp, which redirects T cells to kill tumor cells presenting specific pMHC targets (Damato, B. E., et al., 2023, Nature Reviews Clinical Oncology). Conversely, modulating this interaction is a key strategy in treating autoimmune diseases and preventing transplant rejection, where drugs like Teplizumab target the TCR complex to induce immune tolerance (Simmons, K. M., et al., 2021, Therapeutic Advances in Endocrinology and Metabolism). Safety concerns associated with targeting the TCR–pMHC complex include cytokine release syndrome (CRS) and potential off-target reactivity if the TCR cross-reacts with similar self-peptides (Linette, G. P., et al., 2013, Blood). Therapeutic challenges also include the high degree of HLA polymorphism in the human population, which limits the applicability of MHC-restricted therapies to specific patient subsets. Overall, the TCR–pMHC complex remains a cornerstone of precision immunotherapy, with ongoing research focused on enhancing binding affinity and specificity.

Other names

TCR-pMHC complexT-cell receptor-antigen-MHC complexImmune synapse signaling complexTCR-peptide-HLA complex

T cell receptor agonism, T cell redirection, T cell receptor antagonism, MHC-restricted antigen recognition