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

29 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

Cite this

@article{934290f5ed9c494390dd390929a17681,
title = "Complete modification of TCR specificity and repertoire selection does not perturb a CD8+ T cell immunodominance hierarchy",
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.",
author = "Katherine Kedzierska and Carole Guillonneau and Stephanie Gras and Hatton, {Lauren A} and Richard Webby and Purcell, {Anthony Wayne} and Jamie Rossjohn and Doherty, {Peter C} and Turner, {Stephen J}",
year = "2008",
language = "English",
volume = "105",
pages = "19408 -- 19413",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "49",

}

Complete modification of TCR specificity and repertoire selection does not perturb a CD8+ T cell immunodominance hierarchy. / Kedzierska, Katherine; Guillonneau, Carole; Gras, Stephanie; Hatton, Lauren A; Webby, Richard; Purcell, Anthony Wayne; Rossjohn, Jamie; Doherty, Peter C; Turner, Stephen J.

In: Proceedings of the National Academy of Sciences, Vol. 105, No. 49, 2008, p. 19408 - 19413.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Complete modification of TCR specificity and repertoire selection does not perturb a CD8+ T cell immunodominance hierarchy

AU - Kedzierska, Katherine

AU - Guillonneau, Carole

AU - Gras, Stephanie

AU - Hatton, Lauren A

AU - Webby, Richard

AU - Purcell, Anthony Wayne

AU - Rossjohn, Jamie

AU - Doherty, Peter C

AU - Turner, Stephen J

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

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