Selectively Impaired CD8+ but Not CD4+ T Cell Cycle Arrest during Priming as a Consequence of Dendritic Cell Interaction with Plasmodium-Infected Red Cells

Abstract

Individuals living in malaria-endemic areas show generally low T cell responses to malaria Ags. In this study, we show murine dendritic cell (DC) interaction with parasitized erythrocytes (pRBC) arrested their maturation, resulting in impaired ability to stimulate naive, but not recall T cell responses in vitro and in vivo. Moreover, within the naive T cell population, pRBC-treated DC were selectively deficient in priming CD8+ but not CD4+ T cells. Indeed, DC that had taken up pRBC were shown for the first time to efficiently prime CD4+ T cell responses to a known protective merozoite Ag, MSP4/5. In contrast, impaired priming resulted in decreases in both proliferation and cytokine production by CD8+ T cells. Deficient priming was observed to both a model and a Plasmodium berghei-specific CD8+ T cell epitope. The mechanisms underlying the inability of parasite-treated DC to prime CD8+ T cells were explored. pRBC treatment of DC from wild-type C57BL/6, but not from IL-10 knockout animals, suppressed DC-mediated T cell priming across a Transwell, suggesting active IL-10-dependent suppression. CD8+ T cells were arrested at the G0 stage of the cell cycle after two cell divisions post-Ag stimulation. The proliferation arrest was partially reversible by the addition of IL-2 or IL-7 to responder cultures. These results suggest that in malaria-endemic areas, priming of CD8+ T cell responses may be more difficult to induce via vaccination than the priming of CD4+ T cells. Moreover, pathogens may selectively target the CD8+ T cell arm of protective immunity for immune evasion.

Involvement of CD8+ T cells in protective immunity against murine blood‐stage infection with Plasmodium yoelii 17XL strain

“…In addition, blood-stage parasites seem to evade CD8 1 T cell immunity. That is, dendritic cells that interact with pRBC selectively impair the cell cycles of CD8 1 T cells, but not CD4 1 T cells [29]. In developing vaccines for blood-stage malaria, establishment of strategies for activating CD8 1 T cells specific for the parasites or infected erythrocytes may be essential.…”

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).…”

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

“…Studies have found that dendritic cell (DC) 3 function is compromised during Plasmodium falciparum infections and suggested that this was a factor in the pathogenesis of severe disease (1,2). Similarly, studies of rodent P. berghei infections have also found that DC functions are compromised following infection (3)(4)(5) but other studies have found that DCs from mice infected with P. chabaudi or P. yoelii were fully functional (6,7).…”