Response of the Splenic Dendritic Cell Population to Malaria Infection

Abstract

Dendritic cells, particularly those residing in the spleen, are thought to orchestrate acquired immunity to malaria, but it is not known how the splenic dendritic cell population responds to malaria infection and how this response compares with the responses of other antigen-presenting cells. We investigated this question for Plasmodium chabaudi AS infection in C57BL/6 mice. We found that dendritic cells, defined here by the CD11c marker, migrated from the marginal zone of the spleen into the CD4 ؉ T-cell area within 5 days after parasites entered the bloodstream. This contrasted with the results observed for the macrophage and B-cell populations, which expanded greatly but did not show any comparable migration. Over the same time period dendritic cells showed upregulation of CD40, CD54, and CD86 costimulatory molecules that are required for successful T-cell activation. In dendritic cells, the peak intracellular gamma interferon expression (as shown by fluorescenceactivated cell sorting) was on day 5, 2 days earlier than the peak expression in B-cells or macrophages. These findings show that splenic dendritic cells are actively engaged in the earliest phase of malarial infection in vivo and are likely to be critical in shaping the subsequent immune response.

Interaction of Mouse Dendritic Cells and Malaria-Infected Erythrocytes: Uptake, Maturation, and Antigen Presentation

“…The kinetics of DC uptake of pRBCs closely coincided with the level of IFN-␥ production observed in P. chabaudi-infected B6 mice (19,23). Notably, the peak level of pRBC uptake by splenic DCs observed in this study also coincided with peak numbers of splenic CD11c ϩ DCs expressing IFN-␥ at day 4 -5 following P. chabaudi infection (7,24). For macrophages, levels of nonopsonic phagocytosis also correlate with the ability of infected mice to produce IFN-␥ and treatment of macrophages with IFN-␥ in vitro enhances phagocytosis of pRBCs while treatment with IL-10 inhibits this activity.…”

“…This increased phagocytic activity may be due to an expansion of the DC population in the spleen following P. chabaudi infection (7,24). As the parasite replicates, causing the parasite burden to increase in the blood and more pRBCs to be deposited in the spleen for removal, blood-borne DCs are recruited to the spleen in increasing numbers.…”

“…Both BM-derived and splenic CD11c ϩ DCs exhibited preferential uptake of pRBCs vs nRBCs, and this uptake was dependent in part on actin polymerization, a crucial event in the phagocytosis of large particles. We also hypothesized that the uptake of pRBCs by DCs would induce phenotypic and functional maturation as observed with splenic DCs isolated from mice infected with blood-stage P. chabaudi (7) or P. yoelii (8,9). Indeed, we observed that the selective uptake of pRBCs by splenic DCs was enhanced following infection in vivo and associated with increased expression of MHC class II and costimulatory molecules, IL-12 production, and stimulation of CD4 ϩ T cell proliferation and IFN-␥ production.…”

Cutting Edge: The Acquisition of TLR Tolerance during Malaria Infection Impacts T Cell Activation

“…First, we demonstrate that DCs from infected mice maintain their ability to activate naive T cells throughout infection, an issue that has been controversial. Although some studies show that DCs derived in vitro in the presence of parasitized RBC are dysfunctional (21,22), other work, including our own, found that DCs derived from infected mice are fully mature with respect to expression of costimulatory proteins and T cell activation (11,23,24). One possible explanation for the discrepant results is the lack of T cell-DC interaction in systems where DCs are matured in vitro.…”

Dendritic Cells in Plasmodium Infection

“…Both these findings suggest depressed DC activity. In mouse studies, using murine-compatible Plasmodium species, iRBCs (schizonts or lysates thereof ) were able to stimulate murine mDCs to produce IL-12 and elicit T-cell activation [30], as well as DC surface expression of CD40 and CD86 and migration to T-cells zones in lymphoid tissue in vivo [31]. In contrast with such activation, another group showed hemozoin to impair murine DC function in lymphoid tissue, particularly DC:T-cell clustering, and generated poorly functional T cells [32,33].…”