MHC restriction is structurally encoded by the T cell receptor germline

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Abstract
Summary: MHC restriction — the requirement for αβ T cell receptors (TCRs) to recognize Major Histocompatibility Complex (MHC) molecules when presenting peptide antigens — is a pillar of adaptive immunity. Here, we provide direct structural evidence for TCR germline-encoded recognition of MHC molecules irrespective of antigenic peptide. We engineered “germline-like” TCRs to eliminate CDR3 specificity for peptide, and a molecular clamping strategy to trap ultra-low-affinity complexes with peptide-MHC for cryo-EM. We find that germline-like TCR/pMHC docking modes are identical to wild-type T cell receptors with intact CDR3 loops, across distinct peptide antigens and MHC alleles. Analysis of human TCR repertoires reveals enrichment of specific V genes and Vα-Vβ pairing patterns associated with HLA-A*02 contexts. Thus, the TCR germline encodes the blueprint for MHC restriction, providing a sequence-based framework that could inform computational and AI-driven prediction of TCR specificity.
Funding Information
  • National Institutes of Health (R01AI103867)
  • Cancer Grand Challenges partnership financed by CRUK (CGCATF-2023/100006)
  • National Cancer Institute (OT2CA297242)

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