title: The IL-12 Response of Primary Human Dendritic Cells and Monocytes to Toxoplasma gondii Is Stimulated by Phagocytosis of Live Parasites Rather Than Host Cell Invasion.
abstract: As a major natural host for Toxoplasma gondii, the mouse is widely used for the study of the immune response to this medically important protozoan parasite. However, murine innate recognition of toxoplasma depends on the interaction of parasite profilin with TLR11 and TLR12, two receptors that are functionally absent in humans. This raises the question of how human cells detect and respond to T. gondii. In this study, we show that primary monocytes and dendritic cells from peripheral blood of healthy donors produce IL-12 and other proinflammatory cytokines when exposed to toxoplasma tachyzoites. Cell fractionation studies determined that IL-12 and TNF-α secretion is limited to CD16(+) monocytes and the CD1c(+) subset of dendritic cells. In direct contrast to their murine counterparts, human myeloid cells fail to respond to soluble tachyzoite extracts and instead require contact with live parasites. Importantly, we found that tachyzoite phagocytosis, but not host cell invasion, is required for cytokine induction. Together these findings identify CD16(+) monocytes and CD1c(+) dendritic cells as the major myeloid subsets in human blood-producing innate cytokines in response to T. gondii and demonstrate an unappreciated requirement for phagocytosis of live parasites in that process. This form of pathogen sensing is distinct from that used by mice, possibly reflecting a direct involvement of rodents and not humans in the parasite life cycle.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Department of Biology, Georgetown University, Washington, DC 20057; and.
authors.forename: Kevin W
authors.identifier: http://orcid.org/0000-0001-6236-8060
authors.initials: KW
authors.lastname: Tosh
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Lara
authors.identifier: http://orcid.org/0000-0003-3558-0140
authors.initials: L
authors.lastname: Mittereder
authors.affiliation: Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonne-Annee
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Sara
authors.initials: S
authors.lastname: Hieny
authors.affiliation: Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Thomas B
authors.identifier: http://orcid.org/0000-0001-6887-4941
authors.initials: TB
authors.lastname: Nutman
authors.affiliation: Department of Biology, Georgetown University, Washington, DC 20057; and.
authors.forename: Steven M
authors.identifier: http://orcid.org/0000-0001-5719-7535
authors.initials: SM
authors.lastname: Singer
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; djankovic@niaid.nih.gov.
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
mesh_terms: D018949:Antigens, CD1 / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology* / Q000469:parasitology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D018949:Antigens, CD1; C437944:CD1C protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D006023:Glycoproteins; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12