title: Profoundly Reduced CD1c+ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection.
abstract: Dendritic cells (DCs) are sentinels of the immune system that uniquely prime naive cells and initiate adaptive immune responses. CD1c (BDCA-1) myeloid DCs (CD1c(+) mDCs) highly express HLA-DR, have a broad Toll-like receptor (TLR) repertoire, and secrete immune modulatory cytokines. To better understand immune responses to malaria, CD1c(+) mDC maturation and cytokine production were examined in healthy volunteers before and after experimental intravenous Plasmodium falciparum infection with 150- or 1,800-parasite-infected red blood cells (pRBCs). After either dose, CD1c(+) mDCs significantly reduced HLA-DR expression in prepatent infections. Circulating CD1c(+) mDCs did not upregulate HLA-DR after pRBC or TLR ligand stimulation and exhibited reduced CD86 expression. At peak parasitemia, CD1c(+) mDCs produced significantly more tumor necrosis factor (TNF), whereas interleukin-12 (IL-12) production was unchanged. Interestingly, only the 1,800-pRBC dose caused a reduction in the circulating CD1c(+) mDC count with evidence of apoptosis. The 1,800-pRBC dose produced no change in T cell IFN-γ or IL-2 production at peak parasitemia or at 3 weeks posttreatment. Overall, CD1c(+) mDCs are compromised by P. falciparum exposure, with impaired HLA-DR and CD86 expression, and have an increased capacity for TNF but not IL-12 production. A first prepatent P. falciparum infection is sufficient to modulate CD1c(+) mDC responsiveness, likely contributing to hampered effector T cell cytokine responses and assisting parasite immune evasion.
authors.affiliation: Menzies School of Health Research, Darwin, Australia, and Charles Darwin University, Darwin, Australia jessica.loughland@menzies.edu.au.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Loughland
authors.affiliation: Menzies School of Health Research, Darwin, Australia, and Charles Darwin University, Darwin, Australia.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Minigo
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland, Brisbane, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: Burel
authors.affiliation: Menzies School of Health Research, Darwin, Australia, and Charles Darwin University, Darwin, Australia.
authors.forename: Peta E
authors.initials: PE
authors.lastname: Tipping
authors.affiliation: Menzies School of Health Research, Darwin, Australia, and Charles Darwin University, Darwin, Australia.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Piera
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland, Brisbane, Australia.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Amante
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland, Brisbane, Australia.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.affiliation: Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Good
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland, Brisbane, Australia.
authors.forename: Denise L
authors.initials: DL
authors.lastname: Doolan
authors.affiliation: Menzies School of Health Research, Darwin, Australia, and Charles Darwin University, Darwin, Australia.|Royal Darwin Hospital, Darwin, Australia.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Anstey
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland, Brisbane, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
authors.affiliation: Menzies School of Health Research, Darwin, Australia, and Charles Darwin University, Darwin, Australia.
authors.forename: Tonia
authors.initials: T
authors.lastname: Woodberry
mesh_terms: D000328:Adult; D018949:Antigens, CD1 / Q000032:analysis*; D051940:B7-2 Antigen / Q000032:analysis*; D015331:Cohort Studies; D003713:Dendritic Cells / Q000737:chemistry* / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000032:analysis*; D006684:HLA-DR Antigens / Q000032:analysis*; D064368:Healthy Volunteers; D006801:Humans; D016778:Malaria, Falciparum / Q000473:pathology*; D008297:Male; D010963:Plasmodium falciparum / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018949:Antigens, CD1; D051940:B7-2 Antigen; C437944:CD1C protein, human; C497964:CD86 protein, human; D006023:Glycoproteins; D006684:HLA-DR Antigens; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha