TY - JOUR

T1 - Priming of CD8+ T-cell responses after DNA immunization is impaired in TLR9- and MyD88-deficient mice.

AU - Pavlenko, Maxim

AU - Leder, Christoph

AU - Moreno, Sonia

AU - Levitsky, Victor

AU - Pisa, Pavel

N1 - Funding Information: This study was supported in part by the Cancer Society in Stockholm, the Karolinska Institutes Fund, the Swedish Cancer Society, the EU 6-FP ALLOSTEM (LSHB-CT-2004-502219) and U.S. Department of Defense Prostate Cancer Research Program (PC030958).

PY - 2007/8/21

Y1 - 2007/8/21

N2 - 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.

AB - 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.

KW - Chemistry

KW - Prostate-specific antigen DNA vaccine

KW - CTL response

KW - TLR9

KW - MyD88

UR - http://www.scopus.com/inward/record.url?scp=34447620460&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/8c6c8bba-ff59-39c9-a4f1-061710b25a00/

U2 - 10.1016/j.vaccine.2007.06.016

DO - 10.1016/j.vaccine.2007.06.016

M3 - Journal articles

C2 - 17628235

VL - 25

SP - 6341

EP - 6347

JO - Vaccine

JF - Vaccine

SN - 0264-410X

IS - 34

ER -