HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gallorini, S. Articles by Wack, A. Search for Related Content PubMed PubMed Citation Articles by Gallorini, S. Articles by Wack, A.

Introduction of Zwitterionic Motifs into Bacterial Polysaccharides Generates TLR2 Agonists Able to Activate APCs

Novartis Vaccines Research Center, Siena, Italy.

It was shown previously that bacterial polysaccharides (PS), which naturally contain both positive and negative charges, are able to activate T cells and APCs. However, the vast majority of bacterial PS are anionic and do not have these properties. In this study, we show that chemical introduction of positive charges into naturally anionic bacterial PS confers to the resulting zwitterionic PS (ZPS) the ability to activate pure human monocytes, monocyte-derived dendritic cells, and mouse bone marrow-derived dendritic cells, as do natural bacterial ZPS. Cells are induced to up-regulate MHC class II and costimulatory molecules and to produce cytokines. In mixed monocyte-T cell cocultures, ZPS induce MHC II-dependent T cell proliferation and up-regulation of activation markers. These stimulatory qualities of ZPS disappear when the positive charge is chemically removed from the molecules and thus the zwitterionic motif is destroyed. The ability of natural and chemically derived ZPS to activate APCs can be blocked by anti-TLR2 mAbs, and TLR2 transfectants show reporter gene transcription upon incubation with ZPS. In conclusion, the generation of a zwitterionic motif in bacterial PS confers the ability to activate both APCs and T cells. This finding has important implications for the design of novel polysaccharide vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Institute for Genomics & Bioinformatics, Computational Biology Research Laboratory, University of California, Irvine, CA 92697.

² Address correspondence and reprint requests to Dr. Andreas Wack, Department of Molecular Immunology, Novartis Vaccines Research Center, Via Fiorentina 1, 53100 Siena, Italy. E-mail address: andreas_wack{at}chiron.com

³ Abbreviations used in this paper: PS, polysaccharide; BM-DC, bone marrow-derived dendritic cell; GBS, group B streptococcus; LPL, lipoprotein lipase; Mo-DC, monocyte-derived dendritic cell; NeuNAc, N-acetylneuraminic acid; NMR, nuclear magnetic resonance; Pam₃CSK₄, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]–cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysyl; PSA, Bacteroides fragilis capsular PS A; ZPS, zwitterionic PS.