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Deletion of Flagellin’s Hypervariable Region Abrogates Antibody-Mediated Neutralization and Systemic Activation of TLR5-Dependent Immunity¹

Clément Nempont^*, Delphine Cayet^*, Martin Rumbo, Coralie Bompard, Vincent Villeret and Jean-Claude Sirard^2,*

^* Institut National de la Santé et de la Recherche Médicale, Unité 801, Institut Pasteur de Lille, Université de Lille 2, Institut Fédératif de Recherche 142, Equipe d’Immunité Anti-Microbienne des Muqueuses, Lille, France; Universidad Nacional de La Plata, Laboratorio de Investigaciones en el Sistema Inmune, Facultad de Ciencias Exactas, La Plata, Argentina; and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8161, Institut de Biologie de Lille, Université des Sciences et Technologies de Lille 1, Université de Lille 2, Institut Pasteur de Lille, Institut Fédératif de Recherche 142, Equipe Approche Structurale de la Pathogénèse, Lille, France

TLRs trigger immunity by detecting microbe-associated molecular patterns (MAMPs). Flagellin is a unique MAMP because it harbors 1) an antigenic hypervariable region and 2) a conserved domain involved in TLR5-dependent systemic and mucosal proinflammatory and adjuvant activities. In this study, the contribution of the flagellin domains in TLR5 activation was investigated. We showed that TLR5 signaling can be neutralized in vivo by flagellin-specific Abs, which target the conserved domain. However, deletions of flagellin’s hypervariable region abrogated the protein’s intrinsic ability to trigger the production of neutralizing Abs. The fact that MAMP-specific Abs block TLR-mediated responses shows that this type of neutralization is a novel mechanism for down-regulating innate immunity. The stimulation of mucosal innate immunity and adjuvancy to foreign Ag was not altered by the hypervariable domain deletions. In contrast, this domain is essential to trigger systemic innate immunity, suggesting that there are distinct mechanisms for TLR5 activation in systemic and mucosal compartments. In summary, specific MAMP determinants control the production of neutralizing Abs and the compartmentalization of innate responses.

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 C.N., D.C., and J.C.S. were funded by the Institut National de la Santé et de la Recherche Médicale (including Avenir Grant R02344ES), the Institut Pasteur de Lille, the Région Nord Pas de Calais and FEDER (ARCirémergence), the Franco-Argentinean ECOS-SETCIP Program (A04B03), and the European Community (STREP Grant VaccTIP LSHP-CT-2005-012161).

² Address correspondence and reprint requests to Dr. Jean-Claude Sirard, Institut National de la Santé et de la Recherche Médicale, Unité 801, Equipe d’Immunité Anti-Microbienne des Muqueuses, Institut Pasteur de Lille, 1 rue du Pr Calmette, BP 447, F-59021 Lille, Cedex, France. E-mail address: jean-claude.sirard{at}ibl.fr

³ Abbreviations used in this paper: MAMP, microbe-associated molecular pattern; PMN, polymorphonuclear neutrophil; DC, dendritic cell; i.n., intranasal(ly); BAL, bronchoalveolar lavage; Ct, cycle threshold; RLU, relative luminescence; CT, cholera toxin.