Complete modification of TCR specificity and repertoire selection does not perturb a CD8+ T cell immunodominance hierarchy

Katherine Kedzierska, Carole Guillonneau, Stephanie Gras, Lauren A Hatton, Richard Webby, Anthony Wayne Purcell, Jamie Rossjohn, Peter C Doherty, Stephen J Turner

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

Abstract

Understanding T cell immunodominance hierarchies is fundamental to the development of cellular-based vaccines and immunotherapy. A combination of influenza virus infection in C57BL/6J mice and reverse genetics is used here to dissect the role of T cell antigen receptor (TCR) repertoire in the immunodominant D(b)NP(366)CD8(+) T cell response. Infection with an engineered virus (NPM6A) containing a single alanine (A) mutation at the critical p6 NP(366-374) residue induced a noncross-reactive CD8(+) T cell response characterized by a novel, narrower TCR repertoire per individual mouse that was nonetheless equivalent in magnitude to that generated after WT virus challenge. Although of lower overall avidity, the levels of both cytotoxic T lymphocyte activity and cytokine production were comparable with those seen for the native response. Importantly, the overdominance profile characteristic of secondary D(b)NP(366)-specific clonal expansions was retained for the NPM6A mutant. The primary determinants of immunodominance in this endogenous, non-TCR-transgenic model of viral immunity are thus independent of TCR repertoire composition and diversity. These findings both highlight the importance of effective antigen dose for T cell vaccination and/or immunotherapy and demonstrate the feasibility of priming the memory T cell compartment with engineered viruses to protect against commonly selected mutants viral (or tumor) escape mutants.
Original languageEnglish
Pages (from-to)19408 - 19413
Number of pages5
JournalProceedings of the National Academy of Sciences
Volume105
Issue number49
Publication statusPublished - 2008

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