Infection history and TCR sequence features shape the breadth of TCR cross-reactivity
The T cell receptor (TCR) repertoire enables recognition of a vast array of pathogens, despite containing far fewer unique TCRs than the diversity of encountered epitopes. This potential contradiction is resolved by TCR cross-reactivity, whereby individual TCRs recognize multiple distinct epitopes. However, the features defining broadly cross-reactive TCRs remain poorly understood. Here we systematically analyze TCRs from mice sequentially infected with influenza viruses containing naturally occurring single amino acid variants of the D b NP 366 epitope. We identify 967 unique paired TCR sequences across 18 infection histories and test 22 representative TCRs against 172 epitope variants, yielding 3,784 TCR-epitope interaction measurements. These TCRs exhibit a continuum of cross-reactivity, with infection history influencing both TCR sequence similarity and reactivity profiles. We find specific TCR sequence features associated with broader cross-reactivity, highlighting the interplay between epitope exposure, TCR diversity, and function, and providing insights into CD8 + T cell adaptability, immune memory, and vaccine design.
Authors
- Stefan Schattgen (ORCID: https://orcid.org/0000-0002-6860-5079)
- Paul Glyndwr Thomas (ORCID: https://orcid.org/0000-0001-7955-0256)
- Susu Duan
- Emma Kaitlynn Allen (ORCID: https://orcid.org/0000-0002-3067-751X)
- Walid Awad
- Jessica A Gaevert (ORCID: https://orcid.org/0000-0002-4043-2161)
- Anastasia A. Minervina (ORCID: https://orcid.org/0000-0001-9884-6351)
- Allison M. Kirk (ORCID: https://orcid.org/0000-0002-4286-3678)
- Daniel Luque Duque (ORCID: https://orcid.org/0000-0002-4404-8749)
- Lee-Ann Van de Velde (ORCID: https://orcid.org/0009-0000-6205-1151)
- Andrew J. Fiore-Gartland (ORCID: https://orcid.org/0000-0001-7627-2166)
- Jeremy Chase Crawford (ORCID: https://orcid.org/0000-0003-4096-6048)
- Deryn G. St. James (ORCID: https://orcid.org/0009-0002-7410-5588)
- Carmen Molina-Parı́s (ORCID: https://orcid.org/0000-0001-9828-6737)
- Koshlan Mayer-Blackwell (ORCID: https://orcid.org/0000-0002-1652-4023)
- Philip H Bradley (ORCID: https://orcid.org/0000-0002-0224-6464)
- Mikhail V. Pogorelyy (ORCID: https://orcid.org/0000-0003-0773-1204)
- Aisha Hegab Souquette (ORCID: https://orcid.org/0000-0001-6197-5870)
- Nicholas A. Clark
- Grant Lythe
Institutions
- University of Maryland, Baltimore (US)
- University of Leeds (GB)
- St. Jude Children's Research Hospital (US)
- Los Alamos National Laboratory (US)
- University of Tennessee Health Science Center (US)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Imperial College London (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-10-24
- DOI
- https://doi.org/10.1016/j.celrep.2026.118182
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00