Codification of bidentate pMHC interaction with TCR and its co-receptor

•Functional data implying conjoint TCR and co-receptor binding to pMHC have been structurally established.•Binding modes of CD4 and CD8 to pMHCII and pMHCI, respectively, are distinct.•Mechanobiology has an important role in the TCR–pMHC interaction.•Mechanical force during the TCR–pMHC interaction may optimize exposure of the co-receptor binding site on MHC.

A 1983 Immunology Today rostrum hypothesized that each T cell has two recognition units: a T cell receptor (TCR) complex, which binds antigen associated with a polymorphic region of a MHC molecule (pMHC), and a CD4 or CD8 molecule that binds to a conserved region of that same MHC gene product (class II or I, respectively). Structural biology has since precisely revealed those bidentate pMHC interactions. TCRαβ ligates the membrane-distal antigen-binding MHC platform, whereas CD8 clamps a membrane-proximal MHCI α3 domain loop and CD4 docks to a hydrophobic crevice between MHCII α2 and β2 domains. Here, we review how MHC class-restricted binding impacts signaling and lineage commitment, discussing TCR force-driven conformational transitions that may optimally expose the co-receptor docking site on MHC.