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

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.

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c + Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

“…Reduced HLA-DR expression on mDC has been associated with impaired T cell activation and proliferation (35), suggesting that in an early primary P. vivax infection the T cell response may be shaped by CD16 ϩ mDC rather than CD1c ϩ mDC. In P. falciparum blood-stage CHMI, we recently reported similarly impaired HLA-DR expression on CD1c ϩ mDC, as well as a skewed proinflammatory TNF cytokine response (10). Together, these reports suggest that, at least in a first infection, P. vivax and P. falciparum exert comparable effects on mDC subsets.…”

“…DC are a heterogeneous population of professional antigen-presenting cells that can uniquely prime naive T cells (8). In Plasmodium falciparum CHMI, we previously reported loss of total peripheral blood myeloid DC (mDC) and plasmacytoid DC (pDC) (9), as well as CD1c ϩ mDC dysfunction, characterized by impaired expression of major histocompatibility complex (MHC) class II and skewed proinflammatory cytokine production (10). In areas where malaria is endemic, there is no consensus as to whether P. vivax infection leads to stable pDC and mDC numbers (11), decreases pDC and mDC numbers (12,13), or differentially affects pDC and mDC numbers (14).…”

Characterization of blood dendritic and regulatory T cells in asymptomatic adults with sub-microscopic Plasmodium falciparum or Plasmodium vivax infection

“…The expression of HLA-DR is required by specialist antigen-presenting cells, such as DC, to present foreign antigen to T cells and is commonly used as a marker for DC activation/maturation. In controlled human Plasmodium infection studies, naïve volunteers experimentally infected with P. falciparum displayed reduced circulating pDC and mDC levels, followed by down-regulation of HLA-DR on the surface of pDC [ 22 ] and CD1c + mDC [ 23 ], all occurring at sub-microscopic PCR-level parasitaemia prior to development of patent parasitaemia. Conversely, in both sub-microscopic and patent asymptomatic infections in endemic area residents, the observation of unaltered HLA-DR expression on total circulating DC indicates that DC maturation is not reduced, which may contribute to the maintenance of asymptomatic infection.…”

“…In individuals hospitalized with clinical disease from Plasmodium falciparum and Plasmodium vivax , blood DC are functionally and numerically compromised [ 18 , 19 ] while Treg cells expand [ 20 , 21 ], promoting immune suppression. Similarly, in low-dose experimental P. falciparum blood-stage infection of naïve volunteers, blood DC become non-functional and apoptose at PCR-level parasitaemia below the detection limit of microscopy [ 22 , 23 ]. In contrast, the recent demonstration that adults and children with asymptomatic microscopy-positive P. falciparum or P. vivax infection have increased or retained activation of blood DC and reduced activation of Treg cells [ 14 ], suggests that appropriate DC maturation and less Treg suppression may contribute to the active control of asymptomatic infection.…”

Interdependence Between the Phenotype of Dendritic Cells and Amounts of Blood Proinflammatory Monocytes in Patients With Kidney Cancer

“…), ДИФФЕРЕНЦИРОВАННЫХ IN VITRO ИЗ МОНОЦИТОВ КРОВИ, В ЗАВИСИМОСТИ ОТ КОЛИЧЕСТВА CD14 + CD16 + МОНОЦИТОВ У БОЛЬНЫХ РП, Ме (Q 0,25 -Q 0,75 ) толерогенного эффекта, тогда как CD86 взаимодействует с CD28 и, соответственно, вызывает активацию Т-клеток [22]. HLA-DR относится к МНС II класса и участвует в процессах презентации антигенов [10,19]. Особенностью фенотипа нДК у больных РП с высоким содержанием провоспалительных моноцитов в крови также является увеличение уровней CD86 на CD80 low , HLA-DR на CD80 high клетках, а также молекул CD83 и HLA-DR на CD80 high CD86 high нДК.…”