title: Flagellin induces myeloid-derived suppressor cells: implications for Pseudomonas aeruginosa infection in cystic fibrosis lung disease.
abstract: Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa-infected CF patient ex vivo-isolated as well as flagellin or P. aeruginosa in vitro-generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell-mediated host defense in CF and other P. aeruginosa-associated chronic lung diseases.
authors.affiliation: Department of Pediatrics I, University of Tübingen, Tübingen, 72076 Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rieber
authors.forename: Alina
authors.initials: A
authors.lastname: Brand
authors.forename: Andreas
authors.initials: A
authors.lastname: Hector
authors.forename: Ute
authors.initials: U
authors.lastname: Graepler-Mainka
authors.forename: Michael
authors.initials: M
authors.lastname: Ost
authors.forename: Iris
authors.initials: I
authors.lastname: Schäfer
authors.forename: Irene
authors.initials: I
authors.lastname: Wecker
authors.forename: Davide
authors.initials: D
authors.lastname: Neri
authors.forename: Andreas
authors.initials: A
authors.lastname: Wirth
authors.forename: Lauren
authors.initials: L
authors.lastname: Mays
authors.forename: Sabine
authors.initials: S
authors.lastname: Zundel
authors.forename: Jörg
authors.initials: J
authors.lastname: Fuchs
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Martin
authors.initials: M
authors.lastname: Stern
authors.forename: Michael
authors.initials: M
authors.lastname: Hogardt
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.forename: Joachim
authors.initials: J
authors.lastname: Riethmüller
authors.forename: Michael
authors.initials: M
authors.lastname: Kormann
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
mesh_terms: D000293:Adolescent; D000328:Adult; D001426:Bacterial Proteins / Q000235:genetics; D002478:Cells, Cultured / Q000276:immunology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000150:complications* / Q000382:microbiology; D004198:Disease Susceptibility; D005260:Female; D005407:Flagella / Q000276:immunology / Q000502:physiology; D005408:Flagellin / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate; D008168:Lung / Q000382:microbiology; D008297:Male; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology*; D038042:Myelopoiesis / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000472:pathogenicity*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D055815:Young Adult
chemical_list: D001426:Bacterial Proteins; C527276:CXCR4 protein, human; D017077:Culture Media, Conditioned; D019718:Receptors, CXCR4; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin; C066821:FliM protein, Bacteria