A signaling polypeptide derived from an innate immune adaptor molecule can be harnessed as a new class of vaccine adjuvant.
Modulation of intracellular signaling using cell-permeable polypeptides is a promising technology for future clinical applications. To develop a novel approach to activate innate immune signaling by synthetic polypeptides, we characterized several different polypeptides derived from the caspase recruitment domain (CARD) of IFN-beta promoter stimulator 1, each of which localizes to a different subcellular compartment. Of particular interest was, N'-CARD, which consisted of the nuclear localization signal of histone H2B and the IFN-beta promoter stimulator 1CARD and which localized to the nucleus. This polypeptide led to a strong production of type I IFNs and molecular and genetic analyses showed that nuclear DNA helicase II is critically involved in this response. N'-CARD polypeptide fused to a protein transduction domain (N'-CARD-PTD) readily transmigrated from the outside to the inside of the cell and triggered innate immune signaling. Administration of N'-CARD-PTD polypeptide elicited production of type I IFNs, maturation of bone marrow-derived dendritic cells, and promotion of vaccine immunogenicity by enhancing Ag-specific Th1-type immune responses, thereby protecting mice from lethal influenza infection and from outgrowth of transplanted tumors in vivo. Thus, our results indicate that the N'-CARD-PTD polypeptide belongs to a new class of vaccine adjuvant that directly triggers intracellular signal transduction by a distinct mechanism from those engaged by conventional vaccine adjuvants, such as TLR ligands.
Kobiyama
Kouji
K
Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Takeshita
Fumihiko
F
Ishii
Ken J
KJ
Koyama
Shohei
S
Aoshi
Taiki
T
Akira
Shizuo
S
Sakaue-Sawano
Asako
A
Miyawaki
Atsushi
A
Yamanaka
Yuko
Y
Hirano
Hisashi
H
Suzuki
Koichi
K
Okuda
Kenji
K
D048868:Adaptor Proteins, Signal Transducing / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000145:classification* / Q000235:genetics; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D020169:Caspases / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009036:Moths; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D020169:Caspases; D007252:Influenza Vaccines; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D019444:Vaccines, DNA; C408982:CPG-oligonucleotide; C512612:MAVS protein, mouse