title: Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production.
abstract: Although human CD56(+)CD3(-) natural killer (NK) cells participate in immune responses against microorganisms, their capacity to directly recognize and be activated by pathogens remains unclear. These cells encode members of the Toll-like receptor (TLR) family, involved in innate cell activation on recognition of pathogen-associated molecular patterns (PAMPs). We therefore evaluated whether the 2 bacterial protein PAMPs, the outer membrane protein A from Klebsiella pneumoniae (KpOmpA) and flagellin, which signal through TLR2 and TLR5, respectively, may directly stimulate human NK cells. These proteins induce interferon-gamma (IFN-gamma) production by NK cells and synergize with interleukin-2 (IL-2) and proinflammatory cytokines in PAMP-induced activation. Similar results were obtained using CD56(+)CD3(+) (NKR-expressing) T cells. NK cells from TLR2(-/-) mice fail to respond to KpOmpA, demonstrating TLR involvement in this effect. Defensins are antimicrobial peptides expressed mainly by epithelial cells and neutrophils that disrupt the bacterial membrane, leading to pathogen death. We show that NK cells and NKR-expressing T cells constitutively express alpha-defensins and that KpOmpA and flagellin rapidly induce their release. These data demonstrate for the first time that highly purified NK cells directly recognize and respond to pathogen components through TLRs and evidence defensins as a novel and direct cytotoxic pathway involved in NK cell-mediated protection against microorganisms.
authors.affiliation: Centre d'Immunologie Pierre Fabre, Saint-Julien en Genevois, France.
authors.forename: Anick
authors.initials: A
authors.lastname: Chalifour
authors.forename: Pascale
authors.initials: P
authors.lastname: Jeannin
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gauchat
authors.forename: Aline
authors.initials: A
authors.lastname: Blaecke
authors.forename: Martine
authors.initials: M
authors.lastname: Malissard
authors.forename: Thien
authors.initials: T
authors.lastname: N'Guyen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thieblemont
authors.forename: Yves
authors.initials: Y
authors.lastname: Delneste
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005408:Flagellin / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D023084:alpha-Defensins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D016207:Cytokines; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495346:TLR5 protein, human; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D023084:alpha-Defensins; D005408:Flagellin; C078167:OMPA outer membrane proteins