Fig. 3 |. Force-regulated pMHC conformations determine TCR–MHC dynamic bonds.

a, When a TCR forms a catch bond with an agonistic pMHC (top), increasing force prolongs the bond lifetime at low forces, but the bond changes to a slip bond at high forces. When a TCR forms a slip bond with antagonistic pMHC (bottom), increasing force monotonically shortens the bond lifetime. b, A TCR catch bond with agonistic pMHC is initiated by force-enhanced engagement between the TCR’s CDR3 loops and the peptide’s ‘hotspot’ residues, followed by a force-induced betterment of the complementarity of the MHC–TCR interface (top). Force also induces separation of β₂m from the MHC heavy chain, which leads to MHC extension and rotation of the α₁α₂ domains toward the TCR; this further strengthens the TCR–MHC engagement allosterically. For a weak ligand, force is unable to induce the conformational changes noted above in the pMHC, which leads to slip bonds (bottom). c,d, Cancer-associated somatic mutations (c) or genotype variations (d) encoding mutant HLA molecules may also affect the susceptibility of MHC to conformational changes under force. Examples of the former are HLA-A2 F8V and A236, which form more hydrogen bonds between β₂m and the MHC heavy chains (c). As an example of the latter, HLA-B15 has more hydrogen bonds between β₂m and the MHC heavy chain than does HLA-B44 (d). Diagrams in Fig. 3c,d are modified from ref. ¹⁹.