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.

• Authors: Katherine Kedzierska, Carole Guillonneau, Stephanie Gras, Lauren A Hatton, Richard Webby, Anthony W Purcell, Jamie Rossjohn, Peter C Doherty, Stephen J Turner
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 49 Pg. 19408-13 (Dec 09 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 19047637 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes
• Immunodominant Epitopes
• Influenza Vaccines
• Receptors, Antigen, T-Cell
• Receptors, Antigen, T-Cell, alpha-beta

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, metabolism, virology)
• Epitopes (immunology)
• Genetic Engineering
• Immunodominant Epitopes (immunology, metabolism)
• Influenza A virus (genetics, immunology)
• Influenza Vaccines (immunology)
• Mice
• Mice, Inbred C57BL
• Orthomyxoviridae Infections (immunology)
• Receptors, Antigen, T-Cell (immunology, metabolism)
• Receptors, Antigen, T-Cell, alpha-beta (immunology, metabolism)