Infection history and TCR sequence features shape the breadth of TCR cross-reactivity.

Infection history in sequentially infected mice shapes TCR cross-reactivity, with 967 unique paired TCR sequences showing a continuum of reactivity across 172 epitope variants.

• Why it matters: Broadly cross-reactive TCR features are poorly understood, despite cross-reactivity resolving how limited TCR diversity can recognize many pathogens.
• What they did: Mice were sequentially infected with influenza viruses carrying natural single–amino-acid variants of the D b NP 366 epitope; 22 representative TCRs were tested against 172 variants using 3,784 TCR–epitope interaction measurements.
• The result: Infection history influences TCR sequence similarity and reactivity profiles, and specific TCR sequence features are associated with broader cross-reactivity, informing CD8+ T cell adaptability, immune memory, and vaccine design.