Infection history and TCR sequence features shape the breadth of TCR cross-reactivity
Abstract
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.
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BibTeX
@article{gaevert2026infection,
title = {{Infection history and TCR sequence features shape the breadth of TCR cross-reactivity}},
author = {Jessica A. Gaevert and Koshlan Mayer-Blackwell and Mikhail V. Pogorelyy and Stefan A. Schattgen and Allison M. Kirk and Susu Duan and Lee-Ann Van de Velde and Aisha Hegab Souquette and Walid Awad and Deryn G. St. James and Nicholas A. Clark and Daniel Luque Duque and E. Kaitlynn Allen and Grant Lythe and Carmen Molina-Paris and Jeremy Chase Crawford and Andrew Fiore-Gartland and Philip Bradley and Anastasia A. Minervina and Paul G. Thomas},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2026.118182},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124726012611},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Infection history and TCR sequence features shape the breadth of TCR cross-reactivity
AU - Jessica A. Gaevert
AU - Koshlan Mayer-Blackwell
AU - Mikhail V. Pogorelyy
AU - Stefan A. Schattgen
AU - Allison M. Kirk
AU - Susu Duan
AU - Lee-Ann Van de Velde
AU - Aisha Hegab Souquette
AU - Walid Awad
AU - Deryn G. St. James
AU - Nicholas A. Clark
AU - Daniel Luque Duque
AU - E. Kaitlynn Allen
AU - Grant Lythe
AU - Carmen Molina-Paris
AU - Jeremy Chase Crawford
AU - Andrew Fiore-Gartland
AU - Philip Bradley
AU - Anastasia A. Minervina
AU - Paul G. Thomas
PY - 2026
DA - 2026/10/30
JO - Cell Reports
DO - 10.1016/j.celrep.2026.118182
UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124726012611
AB - 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.
SN - 2211-1247
ER -