title: Critical role for serum opsonins and complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in phagocytosis of Francisella tularensis by human dendritic cells (DC): uptake of Francisella leads to activation of immature DC and intracellular survival of the bacteria.
abstract: Francisella tularensis is one of the most infectious human pathogens known. Although much has been learned about the immune response of mice using an attenuated live vaccine strain (LVS) derived from F. tularensis subspecies holarctica (Type B), little is known about the responses of human monocyte-derived immature dendritic cells (DC). Here, we show that optimal phagocytosis of LVS by DC is dependent on serum opsonization. We demonstrate that complement factor C3-derived opsonins and the major complement receptors expressed by DC, the integrins CR3 (CD11b/CD18) and CR4 (CD11c/CD18), play a critical role in this adhesion-mediated phagocytosis. LVS induced proinflammatory cytokine production and up-regulation of costimulatory surface proteins (CD40, CD86, and MHC Class II) on DC but resisted killing. Once taken up, LVS grew intracellularly, resulting in DC death. DC maturation and cytokine production were induced by direct contact/phagocytosis of LVS or interaction with soluble products of the bacteria, and enhanced activation was seen when LVS was pretreated with serum. Sonicated LVS and supernatants from LVS cultures were potent activators of DC, but LVS LPS failed to activate DC maturation or cytokine production. Serum-treated LVS rapidly induced (within 6 h) a number of cytokines including IL-10, a potent suppressor of macrophage functions and down-regulator of Th1-like responses and the Th1 response inducer IL-12. These results suggest that the simultaneous production of an activating (IL-12, IL-1beta, and TNF-alpha) and a suppressing (IL-10) cytokine profile could contribute to the immunopathogenesis of tularemia.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
authors.forename: Abdelhakim
authors.initials: A
authors.lastname: Ben Nasr
authors.forename: Judith
authors.initials: J
authors.lastname: Haithcoat
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Masterson
authors.forename: John S
authors.initials: JS
authors.lastname: Gunn
authors.forename: Tonyia
authors.initials: T
authors.lastname: Eaves-Pyles
authors.forename: Gary R
authors.initials: GR
authors.lastname: Klimpel
mesh_terms: D001428:Bacterial Vaccines / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D005604:Francisella tularensis / Q000276:immunology*; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000097:blood / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000097:blood / Q000276:immunology*; D009895:Opsonin Proteins / Q000097:blood / Q000502:physiology*; D010587:Phagocytosis / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D001428:Bacterial Vaccines; D016207:Cytokines; D016167:Integrin alphaXbeta2; D016177:Macrophage-1 Antigen; D009895:Opsonin Proteins