Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity.
Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates the innate and adaptive immunity. TLR adaptor molecules play a central role in this cascade; thus, we hypothesized that overexpression of TLR adaptor molecules could mimic infection without any microbial components. Dual-promoter plasmids that carry an antigen and a TLR adaptor molecule such as the Toll-interleukin-1 receptor domain-containing adaptor-inducing beta interferon (TRIF) or myeloid differentiation factor 88 (MyD88) were constructed and administered to mice to determine if these molecules can act as an adjuvant. A DNA vaccine incorporated with the MyD88 genetic adjuvant enhanced antigen-specific humoral immune responses, whereas that with the TRIF genetic adjuvant enhanced cellular immune responses. Incorporating the TRIF genetic adjuvant in a DNA vaccine targeting the influenza HA antigen or the tumor-associated antigen E7 conferred superior protection. These results indicate that TLR adaptor molecules can bridge innate and adaptive immunity and potentiate the effects of DNA vaccines against virus infection and tumors.
Takeshita
Fumihiko
F
Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama 236-0004, Japan. takesita@yokohama-cu.ac.jp
Tanaka
Toshiyuki
T
Matsuda
Tomoko
T
Tozuka
Miyuki
M
Kobiyama
Kouji
K
Saha
Sukumar
S
Matsui
Kiyohiko
K
Ishii
Ken J
KJ
Coban
Cevayir
C
Akira
Shizuo
S
Ishii
Norihisa
N
Suzuki
Koichi
K
Klinman
Dennis M
DM
Okuda
Kenji
K
Sasaki
Shin
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000235:genetics; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007114:Immunization; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000276:Adjuvants, Immunologic; D000956:Antigens, Viral; D019496:Cancer Vaccines; D007252:Influenza Vaccines; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050725:Papillomavirus E7 Proteins; C470409:TICAM1 protein, human; D019444:Vaccines, DNA