Systemic Tumor Necrosis Factor Generated during Lethal Plasmodium Infections Impairs Dendritic Cell Function

Abstract

Dendritic cells (DCs) initiate innate and adaptive immune responses including those against malaria. Although several studies have shown that DC function is normal during malaria, other studies have shown compromised function. To establish why these studies had different findings, we examined DCs from mice infected with two lethal species of parasite, Plasmodium berghei or P. vinckei, and compared them to DCs from nonlethal P. yoelii 17XNL or P. chabaudi infections. These studies found that DCs from only the lethal infections became uniformly mature 7 days after infection and were functionally impaired as they were unable to endocytose latex particles, secrete IL-12, or present OVA to transgenic OTII T cells. These changes coincided with a peak in levels of systemic TNF-α. Because TNF-α is known to mature DCs, we used TNF-KO mice to determine the role of this cytokine in the loss of DC function. In the TNF-KO mice, phenotype, Ag presentation, and IL-12 secretion by DCs were restored to normal following both lethal infections. This study shows that the systemic production of TNF-α contributes to poor DC function during lethal infections. These studies may explain, at least in part, immunosuppression that is associated with malaria.

Blood‐stage Plasmodium berghei infection leads to short‐lived parasite‐associated antigen presentation by dendritic cells

“…It has been suggested that TNF-a may contribute to DC activation and concomitant down-regulation of antigen presentation [14].…”

“…It has been suggested that TNF-a may contribute to DC activation and concomitant down-regulation of antigen presentation [14]. To test this possibility, we infected WT B6 or TNF-a-deficient mice with P. berghei parasites and then examined the proliferation of CD8 1 OT-I T cells in response to immunization with OVAcoated spleen cells (Fig.…”

“…If DC were activated by direct encounter with parasites, then presumably they would capture parasite antigens at the time of activation and effectively present them. On the other hand, if parasitaemia led to release of soluble activatory cytokines such as TNF-a [14], then perhaps DC would be activated prior to capturing parasites and therefore fail to present these antigens.…”

Plasmodium Infection and Endotoxic Shock Induce the Expansion of Regulatory Dendritic Cells

“…In playing such a central role in immunity, it is not surprising that the function of DCs is targeted by the parasite. Indeed, several studies in both humans (5,6) and mice (7)(8)(9)(10)(11)(12)(13)21) have documented changes in DC function in response to Plasmodium. In contrast, other reports have found fully functional DCs when exposed to parasites (14 -20).…”

Dendritic Cells in Plasmodium Infection

“…This DC phenotype may be maintained over the entire course of infection with nonlethal strains of Plasmodium [45], although it is unclear how lethal and nonlethal strains differ with respect to the immune response they generate, and the influence of dose. Later, when parasite densities are peaking, DCs may become refractory to TLR and other signaling events, possibly due to overstimulation or due to TNF-α [46,47], thus abrogating IL-12 and TNF-α secretion, and as capacity to produce IL-10 increases. While secretion of IL-10 may reduce inflammatory responses, a desirable effect when linked to clinical immunity [1], specific immune responses to malaria antigens as well as to other infections and vaccines may be reduced.…”