Somatic genetics of CDR3 control TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

Abstract

The mechanism which adapts the T-cell antigen receptor (TCR) within a given major histocompatibility complex (MHC/HLA) genotype is essential for protection against pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly focused towards a micromolar affinity for their respective peptide (p) plus MHC (pMHC) ligands. Thus, the somatic diversity of the TCR with respect to MHC-restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral solution (from fixed geometry) for any given V domain in TCR bound to pMHC. Solved complexes involving HLA-DR and HLA-DQ, where genetic linkage to the TCR is most profound, were examined in detail. Certain V domains displayed rare geometry within this panel—specifying a restricted rotational probability/volumetric density (dV). Remarkably, hydrogen (H) bond charge-relays distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 contacts on the opposite MHC-II alpha helix. Together, these data suggest that TCR recapitulate dV and specialise target pMHC recognition, i.e., a dynamics alternative to a relative TCR-affinity based mechanism.