Cutting Edge: Conventional Dendritic Cells Are the Critical APC Required for the Induction of Experimental Cerebral Malaria

Abstract

Cerebral malaria (CM) is a serious complication of Plasmodium falciparum infection, causing significant morbidity and mortality among young children and nonimmune adults in the developing world. Although previous work on experimental CM has identified T cells as key mediators of pathology, the APCs and subsets therein required to initiate immunopathology remain unknown. In this study, we show that conventional dendritic cells but not plasmacytoid dendritic cells are required for the induction of malaria parasite-specific CD4+ T cell responses and subsequent experimental CM. These data have important implications for the development of malaria vaccines and the therapeutic management of CM.

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

“…PbA also triggered IFN-a protein production in the spleen, which, in contrast to the poly I:C response, built up gradually over the first 48 h of infection. However, IFN-b protein was not detectable by ELISA in these samples (sensitivity: $1 pg/mL) (data not shown), which is consistent with substantially lower levels of splenic IFN-b mRNA compared to IFN-a mRNA during PbA infection [31]. Together, our data indicate that IFN-a protein is generated in the spleen during PbA infection and that the CD4 1 T-cell transcriptional signature may be shaped by this cytokine.…”

“…The role of IFN-I during blood-stage Plasmodium infection is not clear, although early studies detected IFN activity in the blood after Plasmodium infection [41]. More recently, we also detected IFN-a/b mRNA expression in vivo during PbA infection [31]. In an earlier study, injection of interferon-inducing agents, such as Newcastle disease virus, protected against lethal Plasmodium infection [42].…”

“…By doing so, we identified an IFN-inducible transcriptional signature, potentially mediated by IFN-g and/or IFN-I. While the importance of IFN-g in blood-stage Plasmodium infection has been well established [11,30], a clear role for IFN-I signalling has not yet been elucidated [31,32]. By employing IFN-aR1 À/À mice, which are deficient in IFN-I signalling, we clearly showed that IFN-I indirectly suppressed CD4 1 T-cell responses during blood-stage infection, and impeded control of parasites in two different murine blood-stage malaria models.…”

“…Instead, our data suggest that suppression occurs indirectly, via another cell that impacts on CD4 1 T-cell activation. Given that APCs participate in crucial interactions with T cells during Plasmodium infection [28,31,32], we hypothesize that IFN-I instruct APCs to restrict CD4 1 T-cell responses during blood-stage Plasmodium infection.…”

“…1C) [11,30], the role of IFN-I remains unclear [31,32]. We have previously shown that genes encoding IFN-a and, to a much lesser extent, IFN-b are transcribed in splenic plasmacytoid DCs during PbA infection [31].…”