Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development

• Published in: The Journal of immunology (1950) 2007-12, Vol.179 (12), p.8313-8321
• Main Authors: Radcliffe, Joanna N, Roddick, Joanne S, Stevenson, Freda K, Thirdborough, Stephen M
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation; CD8-Positive T-Lymphocytes - immunology; Cross-Priming; Immunologic Memory; Mice; Mice, Inbred C57BL; Vaccination; Vaccines, DNA - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.179.12.8313

After priming, naive T cells undergo a program of expansion, contraction, and memory formation. Numerous studies have indicated that only a brief period of antigenic stimulation is required to fully commit CD8+ T cells to this program. Nonetheless, the persistence of Ag may modulate the eventual fate of CD8+ T cells. Using DNA delivery, we showed previously that direct presentation primes high levels of effector CD8+ T cells as compared with cross-presentation. One explanation now revealed is that prolonged cross-presentation limits effector cell expansion and function. To analyze this, we used a drug-responsive system to regulate Ag expression after DNA injection. Reducing expression to a single burst expanded greater numbers of peptide-specific effector CD8+ T cells than sustained Ag. Consequences for memory development were assessed after boosting and showed that, although persistent Ag maintained higher numbers of tetramer-positive CD8+ T cells, these expanded less (approximately 4-fold) than those induced by transient Ag expression (approximately 35-fold). Transient expression at priming therefore led to a net higher secondary response. In terms of vaccine design, we propose that the most effective DNA-based CD8+ T cell vaccines will be those that deliver a short burst of Ag.