{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:57:58Z","timestamp":1791194278895,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,29]]},"group-title":"Immunology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01AI103867"],"award-info":[{"award-number":["R01AI103867"]}]},{"name":"Cancer Grand Challenges partnership financed by CRUK","award":["CGCATF-2023\/100006"],"award-info":[{"award-number":["CGCATF-2023\/100006"]}]},{"name":"National Cancer Institute","award":["OT2CA297242"],"award-info":[{"award-number":["OT2CA297242"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>MHC restriction \u2014 the requirement for \u03b1\u03b2 T cell receptors (TCRs) to recognize Major Histocompatibility Complex (MHC) molecules when presenting peptide antigens \u2014 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 \u201cgermline-like\u201d 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\u03b1-V\u03b2 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.<\/jats:p>","DOI":"10.64898\/2026.09.24.754241","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:35:23Z","timestamp":1790706923000},"source":"Crossref","is-referenced-by-count":0,"title":["MHC restriction is structurally encoded by the T cell receptor germline"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6840-5336","authenticated-orcid":false,"given":"Nan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"},{"name":"Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8223-530X","authenticated-orcid":false,"given":"Marta T.","family":"Borowska","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3675-5136","authenticated-orcid":false,"given":"Kevin M.","family":"Jude","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"},{"name":"Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8599-1992","authenticated-orcid":false,"given":"Xiaojing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6392-7608","authenticated-orcid":false,"given":"Chunyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8358-2960","authenticated-orcid":false,"given":"Xinyu","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2939-6787","authenticated-orcid":false,"given":"Liu Daisy","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1077-2712","authenticated-orcid":false,"given":"Rong","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshika","family":"Motiani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7382-3388","authenticated-orcid":false,"given":"Steven C.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5963-2908","authenticated-orcid":false,"given":"Wanlu","family":"Liu","sequence":"additional","affiliation":[{"name":"Centre of Biomedical Systems and Informatics of Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"},{"name":"Institute for Immunity, Transplantation, and Infection, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9273-0278","authenticated-orcid":false,"given":"K. 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