of February 28, 2011This information is current as http://www.jimmunol.org/content/186/1/443doi:10.4049/jimmunol.1001407December 2010; 2011;186;443-452; Prepublished online 3J Immunol LandmannMathias Schmaler, Naja J. Jann, Fabrizia Ferracin and Regine Cell ActivationMyD88-Dependent T−Despite a Strong TLR2 in Systemic InfectionStaphylococcus aureusT and B Cells Are Not Required for Clearing References http://www.jimmunol.org/content/186/1/443.full.html#ref-list-1, 25 of which can be accessed free at:cites 60 articlesThis article Subscriptions http://www.jimmunol.org/subscriptions is online atThe Journal of ImmunologyInformation about subscribing to Permissions http://www.aai.org/ji/copyright.htmlSubmit copyright permission requests atEmail Alerts http://www.jimmunol.org/etoc/subscriptions.shtml/Receive free email-alerts when new articles cite this article. Sign up at Print ISSN: 0022-1767 Online ISSN: 1550-6606.Immunologists, Inc. All rights reserved.by The American Association ofCopyright ©2011 9650 Rockville Pike, Bethesda, MD 20814-3994.The American Association of Immunologists, Inc., is published twice each month byThe Journal of Immunology on February 28, 2011www.jimmunol.orgDownloaded fromThe Journal of ImmunologyT and B Cells Are Not Required for Clearing Staphylococcusaureus in Systemic Infection Despite a StrongTLR2–MyD88-Dependent T Cell ActivationMathias Schmaler, Naja J. Jann, Fabrizia Ferracin, and Regine LandmannStaphylococcus aureus infection elicits through its mature lipoproteins an innate immune response by TLR2–MyD88 signaling,which improves bacterial clearing and disease outcome. The role of dendritic cells (DCs) and T cells in this immune activation andthe function of T and B cells in defense against S. aureus infection remain unclear. Therefore, we first evaluated DC and T cellactivation after infection with S. aureus wild type (WT) and its isogenic mutant, which is deficient in lipoprotein maturation,in vitro. Lipoproteins in viable S. aureus contributed via TLR2–MyD88 to activation of DCs, which promoted the release of IFN-gand IL-17 in CD4+T cells. This strong effect was independent of superantigens and MHC class II. We next evaluated the functionof T cells and their cytokines IFN-g and IL-17 in infection in vivo. Six days after systemic murine infection IFN-g, IL-17, and IL-10 production in total spleen cells were MyD88-dependent and their levels increased until day 21. The comparison of CD32/2,Rag22/2, and C57BL/6 mice after infection revealed that IFN-g and IL-17 originated from T cells and IL-10 originated frominnate immune cells. Furthermore, vaccination of mice to activate T and B cells did not improve eradication of S. aureus fromorgans. In conclusion, S. aureus enhances DC activation via TLR2–MyD88 and thereby promotes TH1 and TH17 cell differenti-ation. However, neither T cells and their MyD88-regulated products, IFN-g and IL-17, nor B cells affected bacterial clearing fromorgans and disease outcome. The Journal of Immunology, 2011, 186: 443–452.Successful immune defenses against pathogens results froman immediate innate and a long-lasting specific response,both processes are tightly connected. Dendritic cells (DCs)are indispensable for the initiation and orchestration of adaptiveimmunity (1, 2). In peripheral organs, immature DCs phagocytoseinvading pathogens and become concurrently activated throughpattern recognition receptors (PRRs) that sense conserved patternson the microorganism. These pathogen-associated molecular pat-terns induce maturation of DCs, including upregulation of MHCclass II and costimulatory surface molecules, switching of che-mokine receptors, and production of inflammatory an d anti-inflammatory cytokines (3). Mature DCs activate T cells in lym-phoid organs (4) and promote the differentiation of CD4+T cellsinto TH1, TH2, and TH17 cells.PRR expression in myeloid DCs includes all surface and in-tracellular TLRs (5–7). TLRs elicit signaling through MyD88 orTRIF proteins, leading to activation of NF-kB and other tran-scription factors (8) with subsequent upregulation of surfacemolecules and production of mediators. TLRs have a potent in-fluence on the quality of THresponses, but mainly the cytokinessecreted by activated DCs program the differentiation of newlyprimed CD4+T cells into TH1, TH2, or TH17 and regulatoryT cells.Staphylococcus aureus is one of the most important pathogenscausing severe systemic infections such as endocarditis or sepsis.Several staphylococcal molecules are known to act as pathogen-associated molecular patterns for TLRs. Infections of cells andmice with S. aureus revealed that lipoproteins trigger the TLR2signaling cascade, which is required for early activation of theinnate immune system (9–12). TLR2 signals exclusively throughMyD88, and cells lacking MyD88 produce no or low levels ofcytokines after recognition of S. aureus (10, 13, 14). The failure ofinflammatory defense appears responsible for the increased sus-ceptibility of these mice to staphylococcal infections (10, 13–16).Besides the unknown spectrum of S. aureus-activated PRRs inDCs, data on the skewing of an S. aureus-induced THcell responseare controversial. One group found a TH2 response after stim-ulation with staphylococcal enterotoxin B through a TLR2-dependent recognition (17), but other studies reported a benefi-cial effect of TH1 responses by depleting CD4+T cells or usingmice deficient in IFN-gR, IL-4, and IL-10 (18–20). In addition,DCs activated by S. aureus peptidoglycan (PGN) promote IL-17production in memory THcells, possibly by amplification ofTLR2-induced IL-23 and IL-1 by NOD2 (21). In the absence ofIL-17, mice were more often colonized with S. aureus (22) andshowed impaired clearance of cutaneous S. aureus infection (23).Nevertheless, IL-17 might also be detrimental to the host, becauseit is known to recruit neutrophils (22), which were found to beattracted by S. aureus that were able to reside in infected organsand survive, although the adaptive immune response with IFN-gproduction was elicited (24).In this study, we examined the pathway of S. aureus-induced DCactivation and of the subsequent T cell differentiation. We used S.aureus strain Newman and an isogenic mutant that was deficient inmature lipoproteins to evaluate their contribution to TLR2 acti-vation. Our results demonstrate that lipoprotein–TLR2–MyD88signaling in DCs was required to initiate the production of IFN-gand IL-17 in naive T
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