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Immunity and Systemic Activation of TLR5-Dependent Neutralization

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Immunity and Systemic Activation of TLR5-Dependent Neutralization Deletion of Flagellin's Hypervariable Region Abrogates Antibody-Mediated Neutralization and Systemic Activation of TLR5-Dependent Immunity This information is current as of September 27, 2021. Clément Nempont, Delphine Cayet, Martin Rumbo, Coralie Bompard, Vincent Villeret and Jean-Claude Sirard J Immunol 2008; 181:2036-2043; ; doi: 10.4049/jimmunol.181.3.2036 http://www.jimmunol.org/content/181/3/2036 Downloaded from References This article cites 40 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/181/3/2036.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Deletion of Flagellin’s Hypervariable Region Abrogates Antibody-Mediated Neutralization and Systemic Activation of TLR5-Dependent Immunity1 Cle´ment Nempont,* Delphine Cayet,* Martin Rumbo,† Coralie Bompard,‡ Vincent Villeret,‡ and Jean-Claude Sirard2* 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 Downloaded from 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 Journal of Immunology, 2008, 181: 2036–2043. http://www.jimmunol.org/ oll-like receptors are instrumental in the coordinated in- presentation to lymphocytes. Consequently, TLR agonists not only duction of innate and adaptive immunity in mammals (1, stimulate “broadly specific” proinflammatory immune responses T 2). Because TLRs are expressed by a broad variety of cell but also enhance the adaptive immune response to defined Ags and types, they are able to trigger immunity throughout the body. Fol- are, thus, considered to be adjuvants (3). Despite these potentially lowing infection by pathogenic microorganisms, TLRs recognize beneficial effects, the systemic toxicity of MAMPs has prompted conserved motifs referred to as microbe-associated molecular pat- efforts to develop derivatives that bias MAMP activity toward ad- terns (MAMPs)3 (1). TLR engagement induces a gene expression juvancy (4). Indeed, engineering molecules with unique properties program dedicated to both innate clearance of and acquired im- is a major challenge in manipulating immune responses. munity to pathogenic microorganisms (2). For instance, TLRs in- Bacterial flagellins (the major flagella components in many bac- by guest on September 27, 2021 duce the production of chemokines that, in turn, specifically attract terial pathogens) are specific, unique agonists for TLR5 activation the polymorphonuclear neutrophils (PMNs) directly involved in (5, 6). The FliC flagellin from Salmonella enterica serovar Typhi- innate microbial clearance. Furthermore, TLRs promote the secre- murium is the paradigm for studies on flagellum structure-func- tion of pleiotropic immune mediators (such as TNF-␣) and the tion, immunity, and TLR5 signaling (6–9). It is a 494-aa protein functional maturation of dendritic cells (DCs) that specialize in Ag with two distinct domains. The amino- and carboxyl-terminal con- served regions (comprising ϳ170 and 90 aa, respectively) form a domain that is essential for TLR5 activation. Furthermore, the mo- *Institut National de la Sante´et de la Recherche Me´dicale, Unite´801, Institut Pasteur tif 89–96 is absolutely required (8–10). The middle (outer) do- de Lille, Universite´ de Lille 2, Institut Fe´de´ratif de Recherche 142, Equipe main of flagellin FliC comprises amino acids from positions 170– d’Immunite´Anti-Microbienne des Muqueuses, Lille, France; †Universidad Nacional de La Plata, Laboratorio de Investigaciones en el Sistema Inmune, Facultad de Cien- 400 and is not mandatory for TLR5 signaling (9, 10). It is cias Exactas, La Plata, Argentina; and ‡Centre National de la Recherche Scientifique, designated as a hypervariable region, since the primary sequences Unite´Mixte de Recherche 8161, Institut de Biologie de Lille, Universite´des Sciences et Technologies de Lille 1, Universite´de Lille 2, Institut Pasteur de Lille, Institut Fe´de´ratif greatly vary in composition and size from one bacterial species to de Recherche 142, Equipe Approche Structurale de la Pathoge´ne`se, Lille, France another. In contrast, it is known that the hypervariable region is Received for publication March 10, 2008. Accepted for publication May 16, 2008. essential for flagellin antigenicity (11, 12). In fact, flagellins’ hy- The costs of publication of this article were defrayed in part by the payment of page pervariable regions carry H-Ag specificity used for serotyping en- charges. This article must therefore be hereby marked advertisement in accordance teropthopathogenic bacteria, especially Salmonella strains. Dele- with 18 U.S.C. Section 1734 solely to indicate this fact. tion of the central domain decreases the flagellins’ antigenicity. 1 C.N., D.C., and J.C.S. were funded by the Institut National de la Sante´etdela For example, the S. typhimurium flagellin FliC⌬ , which is trun- Recherche Me´dicale (including Avenir Grant R02344ES), the Institut Pasteur de 204–292 Lille, the Re´gion Nord Pas de Calais and FEDER (ARCire´mergence), the Franco- cated of 99 aa positioned in the middle part of FliC, is poorly recog- Argentinean ECOS-SETCIP Program (A04B03), and the European Community nized by Abs directed against the whole flagellin (11). The question of (STREP Grant VaccTIP LSHP-CT-2005-012161). whether or not the antigenic and TLR5-activating domains can be 2 Address correspondence and reprint requests to Dr. Jean-Claude Sirard, Institut functionally dissociated had not been addressed until now. National de la Sante´ et de la Recherche Me´dicale, Unite´ 801, Equipe d’Immunite´ Anti-Microbienne des Muqueuses, Institut Pasteur de Lille, 1 rue du Pr Calmette, BP TLR5 agonists are potent activators of systemic and mucosal 447, F-59021 Lille, Cedex, France. E-mail address: [email protected] innate responses. We and others have shown that i.v. injection of 3 Abbreviations used in this paper: MAMP, microbe-associated molecular pattern; PMN, flagellins promotes a systemic response, characterized by the pro- polymorphonuclear neutrophil; DC, dendritic cell; i.n., intranasal(ly); BAL, bronchoal- duction of proinflammatory mediators (such as TNF-␣ or IL-6) veolar lavage; Ct, cycle threshold; RLU, relative luminescence; CT, cholera toxin. and DC activation (5, 6, 13–17). Furthermore, flagellins trigger Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 mucosa-specific innate and adaptive defense mechanisms (18–20). www.jimmunol.org The Journal of Immunology 2037 For instance, epithelial cell lines and lung mucosa up-regulate the grade VII; Sigma-Aldrich) with or without flagellins (1 ␮g) on days 1 and production of chemokines like CXCL8 (IL-8) and CCL20 which, 21. Bronchoalveolar lavages (BALs) and serum were sampled on day 35. in turn, recruit mucosal PMNs and DCs, respectively (18, 19). To assess neutralization, immune and mock sera were heated for 30 min at 56°C to inactivate complement. Serial serum dilutions (in 200 ␮l of PBS) were Various authors have reported that flagellins are potent systemic passively transferred to animals by the i.v. route 1 h before systemic activation and mucosal adjuvants that elicit 1) serum and/or secretory Ab with flagellins. In some experiments, sera were mixed with flagellins diluted in responses and 2) Th1 and Th2 cell responses to both the flagellins PBS and administered i.n. to test mucosal neutralization. themselves and coadministered Ags (14, 17, 21, 22). BALs were collected after the intratracheal injection of 1 ml of PBS with Complete Protease Inhibitor Cocktail (Roche) and clarified by cen- The goal of the present study was to determine whether or not trifugation.
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