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International Immunology Advance Access originally published online on November 1, 2007
International Immunology 2008 20(1):1-9; doi:10.1093/intimm/dxm112
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Immunoadjuvant effects of polyadenylic:polyuridylic acids through TLR3 and TLR7

Takahiro Sugiyama1,2, Katsuaki Hoshino1, Masuyoshi Saito1, Takahiro Yano1, Izumi Sasaki1, Chihiro Yamazaki1, Shizuo Akira2 and Tsuneyasu Kaisho1

1 Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Suehiro-cho 1-7-22, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
2 Department of Host Defense, Research Institute for Microbial Diseases and Akira Innate Immunity Project, Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan

Correspondence to: T. Kaisho; E-mail: tkaisho{at}rcai.riken.jp

Double-stranded RNA (dsRNA) is produced upon viral infection and can activate innate immunity. Polyinosinic:polycytidylic acids [poly(I:C)] is a synthetic mimetic of dsRNA and functions through an endosomal receptor, Toll-like receptor (TLR) 3 or cytosolic receptors. Another type of dsRNA, polyadenylic:polyuridylic acids [poly(A:U)], can also act as an immune adjuvant, but it remains unclear how it exhibits its adjuvant effects. Here, we have characterized the adjuvant effects of poly(A:U). Poly(A:U) could induce both IFN-{alpha} and IL-12p40 from murine bone marrow dendritic cells (DCs). Poly(A:U)-induced IFN-{alpha} production depended on a DC subset, plasmacytoid dendritic cell (pDC), and required TLR7. IL-12p40 was also produced by poly(A:U)-stimulated pDC in a TLR7-dependent manner. In addition to pDC, conventional dendritic cell (cDC) also produced IL-12p40 in response to poly(A:U). This IL-12p40 induction resulted from two cDC subsets, CD24high cDC and CD11bhigh cDC in a TLR3- and TLR7-dependent manner, respectively. In vivo injection of poly(A:U) with antigen led to clonal expansion of and IFN-{gamma} production from antigen-specific CD8+ T cells. Consistent with the in vitro findings, TLR3 and TLR7 were required for the clonal T-cell expansion. Notably, TLR3, rather than TLR7, was critical for generating IFN-{gamma}-producing CD8+ T cells. CD8+ T-cell responses induced by poly(A:U) were independent of type I IFN signaling. Our results demonstrate that poly(A:U) functions as an in vivo immunoadjuvant mainly through TLR3 and TLR7.

Keywords: dendritic cell, double-stranded RNA, immune adjuvant, Toll-like receptor

Transmitting editor: K. Inaba

Received 13 July 2007, accepted 9 October 2007.


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