Priming of CD8+ T-cell responses after DNA immunization is impaired in TLR9- and MyD88-deficient mice.
The plasmid DNA vaccine not only provides expression of the antigen in vivo, but also activates cells of the innate immune system via unmethylated CpG-containing DNA sequences that are recognized by Toll like receptor 9 (TLR9). The requirement of such immunostimulatory activity for induction of CD8+ T-cell responses after DNA immunization is still controversial. In the present study we assessed induction of CD8+ T-cell responses against an immunodominant H-2D(b)-restricted epitope of human prostate-specific antigen in C57Bl/6 (wild-type), TLR9- and MyD88-deficient mice. A single DNA immunization resulted in efficient priming of CD8+ T responses in wild-type mice but not in TLR9- or MyD88-deficient mice. However, priming of CD8+ T cell responses was observed in TLR9-deficient but not in MyD88-deficient mice after multiple DNA immunizations. Moreover, induction of CD8+ T cell responses in TLR9-deficient mice was dependent on the presence of endotoxin contamination in plasmid DNA preparations. Collectively, these results demonstrate that TLR9-dependent immunostimulatory activity of plasmid DNA is essential for priming of CD8+ T-cell responses and that other bacterial compounds present in plasmid DNA preparations and acting via MyD88-dependent pathway could provide alternative signals necessary for priming of CD8+ T cells.
Pavlenko
Maxim
M
Department of Oncology and Pathology, Cancer Center Karolinska, Immune and Gene Therapy Laboratory, Karolinska Institute, Stockholm, Sweden.
Leder
Christoph
C
Moreno
Sonia
S
Levitsky
Victor
V
Pisa
Pavel
P
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000502:physiology*; D019444:Vaccines, DNA / Q000276:immunology*
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019444:Vaccines, DNA; D017430:Prostate-Specific Antigen