MHC restriction is structurally encoded by the T cell receptor germline

Authors

Wang, N., Borowska, M. T., Jude, K. M., Chen, X., Wang, C., Xiang, X., Liu, L. D., Ma, R., Motiani, A., Wilson, S. C., Liu, W., Garcia, K. C.

Abstract

MHC restriction -- the requirement for {beta} 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 V-V{beta} 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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Sep 2026.

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