TCRpeptideMHC

TCRpeptideMHC, often referred to as a TCR–peptide–MHC (pMHC) complex, describes the molecular interaction in which a T cell receptor recognizes a peptide bound within a major histocompatibility complex on an antigen-presenting cell. This recognition is central to adaptive immunity, enabling T cells to distinguish self from non-self and to respond to infected or transformed cells.

Most TCRs are heterodimers formed by alpha and beta chains. The complementary determining regions, particularly CDR3, contact the presented peptide, while CDR1 and CDR2 contact the MHC molecule. The peptide sits in the MHC binding groove; for MHC class I, peptides are typically 8–10 amino acids long and bound to closed-ended grooves; for MHC class II, peptides are longer and bound in an open-ended groove. In physiological processing, class I peptides derive from cytosolic proteins processed by the proteasome and loaded in the endoplasmic reticulum, whereas class II peptides originate from extracellular proteins taken up and loaded in endosomal compartments. The MHC molecule presents the peptide on the cell surface for surveillance by TCRs.

Binding modalities are generally of modest affinity, with dissociation constants in the micromolar to nanomolar range, and the interaction often involves diagonal docking. TCRs can exhibit cross-reactivity, recognizing multiple peptides with shared motifs, balanced by thymic selection to reduce autoimmunity.

Recognition triggers T cell signaling through the CD3 complex, leading to functional responses such as cytokine production and, in CD8+ T cells, cytotoxic activity. In medicine, engineered TCRs targeting tumor-associated pMHC epitopes form the basis of TCR-T cell therapies. Practical challenges include HLA restriction, potential off-target reactivity, and managing affinity to prevent autoimmunity. Research approaches include structural biology, tetramer-based detection, and functional assays to measure activation and specificity.