Protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold

Sophie A Valkenburg, Stephanie Gras, Carole Guillonneau, Nicole L La Gruta, Paul G Thomas, Anthony W Purcell, Jamie Rossjohn, Peter C Doherty, Stephen J Turner, Katherine Kedzierska

Research output: Contribution to journalArticleResearchpeer-review

49 Citations (Scopus)

Abstract

Emergence of a new influenza strain leads to a rapid global spread of the virus due to minimal antibody immunity. Pre-existing CD8(+) T-cell immunity directed towards conserved internal viral regions can greatly ameliorate the disease. However, mutational escape within the T cell epitopes is a substantial issue for virus control and vaccine design. Although mutations can result in a loss of T cell recognition, some variants generate cross-reactive T cell responses. In this study, we used reverse genetics to modify the influenza NP(336-374) peptide at a partially-solvent exposed residue (N->A, NPN3A mutation) to assess the availability, effectiveness and mechanism underlying influenza-specific cross-reactive T cell responses. The engineered virus induced a diminished CD8(+) T cell response and selected a narrowed T cell receptor (TCR) repertoire within two Vbeta regions (Vbeta8.3 and Vbeta9). This can be partially explained by the H-2D(b)NPN3A structure that showed a loss of several contacts between the NPN3A peptide and H-2D(b), including a contact with His155, a position known to play an important role in mediating TCR-pMHC-I interactions. Despite these differences, common cross-reactive TCRs were detected in both the naive and immune NPN3A-specific TCR repertoires. However, while the NPN3A epitope primes memory T-cells that give an equivalent recall response to the mutant or wild-type.....
Original languageEnglish
Pages (from-to)1 - 15
Number of pages15
JournalPLoS Pathogens
Volume6
Issue number8 (e1001039)
DOIs
Publication statusPublished - 2010

Cite this