Preserved Dendritic Cell HLA-DR Expression and Reduced Regulatory T Cell Activation in Asymptomatic Plasmodium falciparum and P. vivax Infection

Kho, Steven; Marfurt, Jutta; Noviyanti, Rintis; Kusuma, Andreas; Piera, Kim A.; Burdam, Faustina Helena; Kenangalem, Enny; Lampah, Daniel A.; Engwerda, Christian; Poespoprodjo, Jeanne Rini; Price, Ric N.; Anstey, Nicholas M.; Minigo, Gabriela; Woodberry, Tonia

doi:10.1128/iai.00226-15

Cited by 30 publications

(61 citation statements)

References 49 publications

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“…The total blood mDCs are reduced in experimental infections (11), and CD1c ϩ mDCs are reduced in acute malaria (12,46), but importantly in areas of malaria endemicity, there is a preservation of blood CD1c ϩ mDC in asymptomatic carriers of P. falciparum with patent parasitemia (46). Interestingly, after the 150-pRBC infections the circulating CD1c ϩ mDCs were stable.…”

Section: P Falciparum Compromised Cd86 Expression On Cd1cmentioning

confidence: 85%

Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

et al. 2016

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dDendritic 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-␥ 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.

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Section: P Falciparum Compromised Cd86 Expression On Cd1cmentioning

confidence: 85%

Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

et al. 2016

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“…Regulatory T cells often expand during infection (208). Their principal role is to control the excessive pro-inflammatory response which depending on the parasite species may be beneficial or detrimental (209–211). Taken together, these mechanisms leading to immunosuppression are likely to favor survival of the parasite in the host and prevent the establishment of an efficient memory response.…”

Section: Immunosuppressionmentioning

confidence: 99%

Malaria Parasites: The Great Escape

Rénia

Goh

2016

Front. Immunol.

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Parasites of the genus Plasmodium have a complex life cycle. They alternate between their final mosquito host and their intermediate hosts. The parasite can be either extra- or intracellular, depending on the stage of development. By modifying their shape, motility, and metabolic requirements, the parasite adapts to the different environments in their different hosts. The parasite has evolved to escape the multiple immune mechanisms in the host that try to block parasite development at the different stages of their development. In this article, we describe the mechanisms reported thus far that allow the Plasmodium parasite to evade innate and adaptive immune responses.

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“…There is a consensus that blood pDC numbers decline in acute clinical malaria 18–22 . However, it is unclear whether pDC loss is due to migration 18 or cell death 19 .…”

Section: Introductionmentioning

confidence: 99%

Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation

Loughland

Minigo

Sarovich

et al. 2017

Sci Rep

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Plasmacytoid dendritic cells (pDC) are activators of innate and adaptive immune responses that express HLA-DR, toll-like receptor (TLR) 7, TLR9 and produce type I interferons. The role of human pDC in malaria remains poorly characterised. pDC activation and cytokine production were assessed in 59 malaria-naive volunteers during experimental infection with 150 or 1,800 P. falciparum-parasitized red blood cells. Using RNA sequencing, longitudinal changes in pDC gene expression were examined in five adults before and at peak-infection. pDC responsiveness to TLR7 and TLR9 stimulation was assessed in-vitro. Circulating pDC remained transcriptionally stable with gene expression altered for 8 genes (FDR < 0.07). There was no upregulation of co-stimulatory molecules CD86, CD80, CD40, and reduced surface expression of HLA-DR and CD123 (IL-3R-α). pDC loss from the circulation was associated with active caspase-3, suggesting pDC apoptosis during primary infection. pDC remained responsive to TLR stimulation, producing IFN-α and upregulating HLA-DR, CD86, CD123 at peak-infection. In clinical malaria, pDC retained HLA-DR but reduced CD123 expression compared to convalescence. These data demonstrate pDC retain function during a first blood-stage P. falciparum exposure despite sub-microscopic parasitaemia downregulating HLA-DR. The lack of evident pDC activation in both early infection and malaria suggests little response of circulating pDC to infection.

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Preserved Dendritic Cell HLA-DR Expression and Reduced Regulatory T Cell Activation in Asymptomatic Plasmodium falciparum and P. vivax Infection

Cited by 30 publications

References 49 publications

Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

Malaria Parasites: The Great Escape

Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation

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Preserved Dendritic Cell HLA-DR Expression and Reduced Regulatory T Cell Activation in Asymptomatic Plasmodium falciparum and P. vivax Infection

Cited by 30 publications

References 49 publications

Profoundly Reduced CD1c + Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

Profoundly Reduced CD1c + Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

Malaria Parasites: The Great Escape

Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation

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Product

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Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection