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Antigenic Epitopes Fused to Cationic Peptide Bound to Oligonucleotides Facilitate Toll-Like Receptor 9-Dependent, but CD4⁺ T Cell Help-Independent, Priming of CD8⁺ T Cells¹

Reinhold Schirmbeck^2,*, Petra Riedl^*, Rinaldo Zurbriggen, Shizuo Akira and Jörg Reimann^*

^* Department of Medical Microbiology and Immunology, University of Ulm, Ulm, Germany; Pevion Biotech, Bern, Switzerland; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

A priority in current vaccine research is the development of adjuvants that support the efficient priming of long-lasting, CD4⁺ T cell help-independent CD8⁺ T cell immunity. Oligodeoxynucleotides (ODN) with immune-stimulating sequences (ISS) containing CpG motifs facilitate the priming of MHC class I-restricted CD8⁺ T cell responses to proteins or peptides. We show that the adjuvant effect of ISS⁺ ODN on CD8⁺ T cell priming to large, recombinant Ag is enhanced by binding them to short, cationic (arginine-rich) peptides that themselves have no adjuvant activity in CD8⁺ T cell priming. Fusing antigenic epitopes to cationic (8- to 10-mer) peptides bound to immune-stimulating ISS⁺ ODN or nonstimulating NSS⁺ ODN (without CpG-containing sequences) generated immunogens that efficiently primed long-lasting, specific CD8⁺ T cell immunity of high magnitude. Different MHC class I-binding epitopes fused to short cationic peptides of different origins showed this adjuvant activity. Quantitative ODN binding to cationic peptides strikingly reduced the toxicity of the latter, suggesting that it improves the safety profile of the adjuvant. CD8⁺ T cell priming supported by this adjuvant was Toll-like receptor 9 dependent, but required no CD4⁺ T cell help. ODN (with or without CpG-containing sequences) are thus potent Th1-promoting adjuvants when bound to cationic peptides covalently linked to antigenic epitopes, a mode of Ag delivery prevailing in many viral nucleocapsids.

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