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International Immunology Advance Access originally published online on February 7, 2007
International Immunology 2007 19(3):297-304; doi:10.1093/intimm/dxl146
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Immunostimulatory RNA is a potent inducer of antigen-specific cytotoxic and humoral immune response in vivo

Svetlana Hamm1, Antje Heit1, Martina Koffler1, Katharina M. Huster1, Shizuo Akira2, Dirk H. Busch1, Herrmann Wagner1 and Stefan Bauer3

1 Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstrasse 30, 81675 München, Germany
2 Akira Innate Immunity Project, ERATO, Japan Science and Technology Corporation (JST), Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
3 Institut für Immunologie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 2, 35042 Marburg, Germany

Correspondence to: S. Bauer; E-mail: stefan.bauer{at}staff.uni-marburg.de

Single-stranded RNA stimulates immune cells and induces the secretion of pro-inflammatory cytokines and type I IFN. As adjuvant RNA can induce a Th2 type of humoral response, however, its potency in the induction of cytotoxic T cells in vivo has not been analyzed. Here we show that immunization with the antigen ovalbumin (OVA) and the adjuvant phosphodiester RNA complexed to the cationic lipid N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate (DOTAP) induced a Toll-like receptor-7-dependent cytotoxic T cell and humoral response. Staining with SIINFEKL-Kb tetramers demonstrated the induction of antigen-specific T cells that were functional in in vivo cytotoxic T cell assays against SIINFEKL-loaded target cells. In infection experiments with OVA-secreting Listeria monocytogenes, the cytotoxic T cell response strongly reduced the bacterial load in liver and spleen. The RNA-driven humoral response was characterized by OVA-specific antibodies of the IgG1 isotype whereas CpG-DNA induced antigen-specific antibodies of the IgG2a (BALB/c) or IgG2c (C57BL/6) isotype. Furthermore, stimulation with RNA did not induce splenomegaly, a common feature of CpG-DNA-driven immune activation in mice. Taken together, our data confirm that RNA can be used as a safe adjuvant and induces a strong antibody response of the IgG1 isotype. Additionally, we demonstrate that RNA induces an antigen-specific immunity characterized by a potent cytotoxic T cell response to infection.

Keywords: IgG isotype, innate immunity, ovalbumin, Toll-like receptors, vaccination

Transmitting editor: R. Medzhitov

Received 6 October 2006, accepted 21 December 2006.


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