期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 49, 页码 19408-19413出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0810274105
关键词
avidity; viral escape; pMHC structure; TCR diversity; reverse genetics
资金
- National Health and Medical Research Council [AI454595, AI508929, AI454312]
- University of Melbourne Early Career Researcher
- National Institutes of Health [AI170251]
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 NP366-374 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 (DNP366)-N-b-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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