Atypical activation of dendritic cells by Plasmodium falciparum

Abstract

Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by , the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1β, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naïve US donors and malaria-experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-α secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with-infected erythrocytes activated antigen-specific naïve CD4 T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to exhibited a transcriptional program distinct from a classical LPS response, pointing to unique -induced activation pathways that may explain the uncharacteristic immune response to malaria.

Malaria inflammation by xanthine oxidase‐produced reactive oxygen species

“…Malaria induces an extremely high inflammatory response which, coupled to the sequestration of Plasmodium falciparum ‐infected red blood cells (iRBC), plays a key role in the life‐threatening pathologies associated with this disease (Clark, ; Clark et al , ). A remarkable paradox in malaria research is that the strong inflammatory cytokine response and high fevers in patients cannot be modeled in vitro , where incubation of the parasite with immune cells results in little to no response in immune cells, such as macrophages (Scragg et al , ; Couper et al , ; Zhou et al , ) or dendritic cells (Elliott et al , ; Giusti et al , ; Götz et al , ). It is important to note that older publications showing in vitro inflammation were latter attributed to mycoplasma contamination of the cultures (Rowe et al , ).…”

Immune effector mechanisms in malaria: An update focusing on human immunity

“…IFNα‐mediated pDC crosstalk with cDC1 (CD141+, BDCA3+) enhance phagocytosis of parasitized‐RBCs or free merozoites, whereby cDC1 become MHC Class II restricted antigen‐presenting cells (APCs) that secrete cytokines to instruct naïve CD4+ T cell differentiation or cross‐present antigens via the alternate pathway for MHC I‐restricted induction of cytotoxic CD8+ T cells, which has been described for P. falciparum . Transcriptional profiling of human immune cells has also begun to reveal atypical interactions between DCs and parasitized‐RBCs . Newly named “ bona fide” DCs co‐cultured in vitro with parasitized‐RBCs expressed low levels of inflammatory Th1 cytokines (ie, IL1β, IL6, IL10 and TNF) and yet were still able to activate naïve CD4+ T cells to proliferate and secrete Th1 cytokines (ie, IFNγ and TNF).…”

“…This contradiction puts into question mechanisms of “DC suppression” during malaria (reviewed in ). Of note, P. falciparum ‐induced transcriptional profiles were compared to publically available transcriptomes of DCs stimulated by 13 microbial vaccines and four viral vaccines appeared to regulate DCs in the same manner as P. falciparum . Given more sophisticated subclassifications of DCs and new techniques to evaluate cell‐to‐cell communication (directly or indirectly), studies of human DCs have the potential to lead to discoveries related to heterogeneity in adaptive T cell immunity for the different stages of P. falciparum …”

“…116 Transcriptional profiling of human immune cells has also begun to reveal atypical interactions between DCs and parasitized-RBCs. 115,117 Newly named "bona fide" DCs co-cultured in vitro with parasitized-RBCs expressed low levels of inflammatory Th1 cytokines (ie, IL1β, IL6, IL10 and TNF) and yet were still able to activate naïve CD4+ T cells to proliferate and secrete Th1 cytokines (ie, IFNγ and TNF). This contradiction puts into question mechanisms of "DC suppression" during malaria (reviewed in 115,118 ).…”

“…We also postulate that repeated P. falciparum infections play a role in the development of unconventional CD8 dim T cells (dark yellow cells), which expresses GrzB at high levels in lieu of cytokines/chemokines (H2) and four viral vaccines appeared to regulate DCs in the same manner as P. falciparum. 117 Given more sophisticated subclassifications of DCs and new techniques to evaluate cell-to-cell communication (directly or indirectly), studies of human DCs have the potential to lead to discoveries related to heterogeneity in adaptive T cell immunity for the different stages of P. falciparum. 118…”