Conventional CD11chigh Dendritic Cells Are Important for T Cell Priming during the Initial Phase of Plasmodium yoelii Infection, but Are Dispensable at Later Time Points.

Kristina Ueffing,Hanna Abberger,Kai Matuschewski,Wiebke Hansen,Astrid M Westendorf,Jan Buer

doi:10.3389/fimmu.2017.01333

Kristina Ueffing, Hanna Abberger + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2017.01333

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Abstract

Dendritic cells (DCs) are highly specialized antigen-presenting cells that orchestrate adaptive immune responses to pathogens. During malaria infection pro- and anti-inflammatory T cell responses have to be tightly balanced to ensure parasite clearance without induction of severe immune pathologies. However, the precise role of CD11chigh DCs in this process is still discussed controversially. Here, we demonstrate that long-term depletion of conventional CD11chigh DCs in Plasmodium yoelii (P. yoelii)-infected diphtheria toxin (DT)-treated RosaiDTR/CD11c-cre mice interferes with the activation of CD8+ and CD4+ T cells as well as CD4+Foxp3+ regulatory T cells at early time points during infection. Moreover, systemic levels of the pro-inflammatory cytokines IFN-γ and TNF-α were decreased in P. yoelii-infected mice deficient for CD11chigh DCs compared to infected RosaiDTR controls. To further elucidate the importance of CD11chigh DCs during the later phase of infection, we treated RosaiDTR/CD11c-cre and control mice with DT only from day 4 of P. yoelii infection onward. Strikingly, this approach had no impact on the activation and IFN-γ production of CD4+ and CD8+ effector T cells. These results indicate that CD11chigh DCs play a crucial role in eliciting effector T cell responses during the initial phase, but are dispensable during ongoing infection with P. yoelii.

Highlights

Malaria is still one of the most important infectious diseases in humans worldwide
To study the impact of conventional CD11chigh dendritic cell (DC) on the T cell response elicited by infection with P. yoelii, we made use of RosaiDTRtg/tg/CD11c-cretg/wt mice
We detected significant reduced frequencies of CD11cintCD11b−Ly6C+B220+ plasmacytoid DCs in diphtheria toxin (DT)-treated non-infected and infected RosaiDTR/ CD11c-cre mice in contrast to RosaiDTR littermates (Figure 1E)

Summary

Introduction

Malaria is still one of the most important infectious diseases in humans worldwide. Mostly, children under 5 years of age have a high risk to die from malaria infections and an effective vaccine is still missing. It is well established that the immune response to the malaria parasite Plasmodium (P.) has to be tightly regulated to enable efficient pathogen clearance without excessive immune activation that might result in exacerbated tissue damage and increased mortality [1, 2]. During the blood-stage of infection, CD4+ T cells play a critical role in balancing the immune response. Impact of DCs on P. yoelii Infection effector T cells provide help to B cells and activate immunity, immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs) have been shown to expand in patients infected with P. falciparum [3, 4] and P. vivax [5] and in different malaria mouse models [6,7,8]. Depletion of Tregs resulted in elevated T cell responses accompanied by enhanced pathogen clearance demonstrating their immunosuppressive function in the course of Plasmodium infection [6]. Which mechanisms and cell types are involved in activation and controlling T cell responses to keep the balance between effective parasite clearance and harmful pathological responses is still discussed controversially

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