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.