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

Loughland, Jessica R.; Minigo, Gabriela; Sarovich, Derek S.; Field, Matthew A.; Tipping, Peta; de, Marcela Montes; Piera, Kim A.; Amante, Fiona H.; Barber, Bridget E.; Grigg, Matthew J.; William, Timothy; Good, Michael F.; Doolan, Denise L.; Engwerda, Christian; Anstey, Nicholas M.; McCarthy, James S.; Woodberry, Tonia

doi:10.1038/s41598-017-02096-2

Cited by 26 publications

(39 citation statements)

References 62 publications

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“…Our data support a model in which B cells serve as the primary APC during blood-stage Plasmodium infection. The distinctive role for B cells in this context is likely influenced by diminished DC function (Götz et al, 2017;Loughland et al, 2017;Pinzon-Charry et al, 2013;Urban et al, 1999;Woodberry et al, 2012;Wykes et al, 2007) and/or the splenic disruption associated with this infection (Cadman et al, 2008). The Plasmodium-specific CD4 + T cell population acquires a stable CXCR5 + Tfh phenotype at acute time points during infection that is maintained late into the memory response.…”

Section: Resultsmentioning

confidence: 99%

“…Of interest, several studies have noted an increase in the circulating cDC1 population in humans following Plasmodium infection, coupled with a significant decrease in the surface expression of the human MHC II molecule HLA-DR (Arama et al, 2011;Guermonprez et al, 2013;Urban et al, 2006). Many have reported a decrease in antigen uptake and presentation by DCs in both mouse and human studies (Götz et al, 2017;Loughland et al, 2017;Pinzon-Charry et al, 2013;Urban et al, 1999;Woodberry et al, 2012;Wykes et al, 2007). Others described a specific dysfunction of the cDCs to prime CD4 + T cells due to the type I IFN signaling induced early in infection (Haque et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…However, these studies used CD11c as the cDC marker, which is also upregulated by activated B cells, CD4 + T cells, CD8 + T cells, natural killer (NK) cells, and NK T cells (Rubtsov et al, 2011;Satpathy et al, 2012;Sullivan et al, 2015;Weiss et al, 2009). In other studies, DCs have been shown to have dysfunctional responses during blood-stage Plasmodium, including a reduced capacity for antigen uptake and antigen presentation (Götz et al, 2017;Loughland et al, 2017;Pinzon-Charry et al, 2013;Urban et al, 1999;Woodberry et al, 2012;Wykes et al, 2007).…”

Section: Epitope-specific Cd4 + T Cells Express Cxcr5 At Both Acute Amentioning

confidence: 99%

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B cells are sufficient to prime the dominant CD4+ Tfh response to Plasmodium infection

Arroyo

Pepper

2019

Journal of Experimental Medicine

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CD4+ T follicular helper (Tfh) cells dominate the acute response to a blood-stage Plasmodium infection and provide signals to direct B cell differentiation and protective antibody expression. We studied antigen-specific CD4+ Tfh cells responding to Plasmodium infection in order to understand the generation and maintenance of the Tfh response. We discovered that a dominant, phenotypically stable, CXCR5+ Tfh population emerges within the first 4 d of infection and results in a CXCR5+ CCR7+ Tfh/central memory T cell response that persists well after parasite clearance. We also found that CD4+ T cell priming by B cells was both necessary and sufficient to generate this Tfh-dominant response, whereas priming by conventional dendritic cells was dispensable. This study provides important insights into the development of CD4+ Tfh cells during Plasmodium infection and highlights the heterogeneity of antigen-presenting cells involved in CD4+ T cell priming.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Epitope-specific Cd4 + T Cells Express Cxcr5 At Both Acute Amentioning

confidence: 99%

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B cells are sufficient to prime the dominant CD4+ Tfh response to Plasmodium infection

Arroyo

Pepper

2019

Journal of Experimental Medicine

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“…A decrease in HLA-DR surface expression, which might lead to suboptimal T cell priming, has been described in acute malaria patients [28,[37][38][39][40][41][42]. Therefore, we asked whether altered HLA-DR expression was associated with asymptomatic P. falciparum-infection.…”

Section: Study Cohortmentioning

confidence: 97%

Dendritic cell responses to Plasmodium falciparum in a malaria-endemic setting

Turner

Arama

Ongoïba

et al. 2020

Preprint

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Background: Plasmodium falciparum causes the majority of malaria cases world-wide, mostly affecting children in sub-Saharan Africa. Non-sterile clinical immunity that protects from symptoms develops slowly and is relatively short-lived. Moreover, current malaria vaccine candidates fail to induce durable high-level protection in endemic settings, possibly due to the immunomodulatory effects of the malaria parasite itself. Because dendritic cells play a crucial role in initiating immune responses, here we sought to better understand the impact of cumulative malaria exposure as well as concurrent P. falciparum infection on dendritic cell phenotype and function.Methods: In this cross-sectional study we assessed the phenotype and function of dendritic cells freshly isolated from peripheral blood samples of Malian adults with a lifelong history of malaria exposure who were either uninfected (n=27) or asymptomatically infected with P. falciparum (n=8). Additionally, we measured plasma cytokine and chemokine levels in these adults and in Malian children (n=19) with acute symptomatic malaria.Results: With the exception of lower plasmacytoid dendritic cell frequencies in asymptomatically infected Malian adults, peripheral blood dendritic cell subset frequencies and HLA-DR surface expression did not differ by infection status. Peripheral blood myeloid dendritic cells of uninfected Malian adults responded to in vitro stimulation with P. falciparum blood-stage parasites by up-regulating the costimulatory molecules HLA-DR, CD80, CD86 and CD40 and secreting IL-10, CXCL9 and CXCL10. In contrast, myeloid dendritic cells of asymptomatically infected Malian adults exhibited no significant responses above the uninfected red blood cell control. IL-10 and CXCL9 plasma levels were elevated in both asymptomatic adults and children with acute malaria.Conclusions: Our findings indicate that myeloid dendritic cells of uninfected adults with a lifelong history of malaria exposure are able to up-regulate co-stimulatory molecules and produce cytokines. Whether mDCs of malaria-exposed individuals are efficient antigen-presenting cells capable of mounting an appropriate immune response remains to be determined. The data also highlights IL-10 and CXCL9 as important factors in both asymptomatic and acute malaria and add to our understanding of asymptomatic P. falciparum infections in malaria-endemic areas.

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“…In addition, whether pDC‐ or cDC‐derived IFN‐ α / β production occurs mainly in the bone marrow, blood or spleen during blood‐stage infection remains an important question. Finally, although some assessment of IFN‐ α / β production during blood‐stage Plasmodium infection has been attempted in humans, it has been challenging to observe this occurring directly ex vivo . It will be important to determine the cellular and molecular basis of IFN‐ α / β production in human blood‐stage Plasmodium infection.…”

Section: Type I Ifn Production During Blood‐stage Malariamentioning

confidence: 99%

Effects of type I interferons in malaria

Sebina

Haque

2018

Immunology

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Type I interferons (IFNs) are a family of cytokines with a wide range of biological activities including anti-viral and immune-regulatory functions. Here, we focus on the protozoan parasitic disease malaria, and examine the effects of type I IFN-signalling during Plasmodium infection of humans and experimental mice. Since the 1960s, there have been many studies in this area, but a simple explanation for the role of type I IFN has not emerged. Although epidemiological data are consistent with roles for type I IFN in influencing malaria disease severity, functional proof of this remains sparse in humans. Several different rodent-infective Plasmodium species have been employed in in vivo studies of parasite-sensing, experimental cerebral malaria, lethal malaria, liver-stage infection, and adaptive T-cell and B-cell immunity. A range of different outcomes in these studies suggests a delicately balanced, multi-faceted and highly complex role for type I IFN-signalling in malaria. This is perhaps unsurprising given the multiple parasite-sensing pathways that can trigger type I IFN production, the multiple isoforms of IFN-α/β that can be produced by both immune and non-immune cells, the differential effects of acute versus chronic type I IFN production, the role of low level 'tonic' type I IFN-signalling, and that signalling can occur via homodimeric IFNAR1 or heterodimeric IFNAR1/2 receptors. Nevertheless, the data indicate that type I IFN-signalling controls parasite numbers during liver-stage infection, and depending on host-parasite genetics, can be either detrimental or beneficial to the host during blood-stage infection. Furthermore, type I IFN can promote cytotoxic T lymphocyte immune pathology and hinder CD4 T helper cell-dependent immunity during blood-stage infection. Hence, type I IFN-signalling plays highly context-dependent roles in malaria, which can be beneficial or detrimental to the host.

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

Cited by 26 publications

References 62 publications

B cells are sufficient to prime the dominant CD4+ Tfh response to Plasmodium infection

B cells are sufficient to prime the dominant CD4+ Tfh response to Plasmodium infection

Dendritic cell responses to Plasmodium falciparum in a malaria-endemic setting

Effects of type I interferons in malaria

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