MHC restriction is structurally encoded by the T cell receptor germline
- 1Stanford University School of Medicine; Howard Hughes Medical Institute
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.
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BibTeX
@misc{wang2026restriction,
title = {{MHC restriction is structurally encoded by the T cell receptor germline}},
author = {N. Wang and M. T. Borowska and K. M. Jude and X. Chen and C. Wang and X. Xiang and L. D. Liu and R. Ma and A. Motiani and S. C. Wilson and W. Liu and K. C. Garcia},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754241},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754241v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - MHC restriction is structurally encoded by the T cell receptor germline
AU - N. Wang
AU - M. T. Borowska
AU - K. M. Jude
AU - X. Chen
AU - C. Wang
AU - X. Xiang
AU - L. D. Liu
AU - R. Ma
AU - A. Motiani
AU - S. C. Wilson
AU - W. Liu
AU - K. C. Garcia
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754241
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754241v1
AB - 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.
ER -