CD4⁺CD25⁺Foxp3⁺Regulatory T Cells, Dendritic Cells, and Circulating Cytokines in Uncomplicated Malaria: Do Different Parasite Species Elicit Similar Host Responses?

Abstract

Clearing blood-stage malaria parasites without inducing major host pathology requires a finely tuned balance between pro-and anti-inflammatory responses. The interplay between regulatory T (Treg) cells and dendritic cells (DCs) is one of the key determinants of this balance. Although experimental models have revealed various patterns of Treg cell expansion, DC maturation, and cytokine production according to the infecting malaria parasite species, no studies have compared all of these parameters in human infections with Plasmodium falciparum and P. vivax in the same setting of endemicity. Here we show that during uncomplicated acute malaria, both species induced a significant expansion of CD4 ؉ CD25 ؉ Foxp3 ؉ Treg cells expressing the key immunomodulatory molecule CTLA-4 and a significant increase in the proportion of DCs that were plasmacytoid (CD123 ؉ ), with a decrease in the myeloid/plasmacytoid DC ratio. These changes were proportional to parasite loads but correlated neither with the intensity of clinical symptoms nor with circulating cytokine levels. One-third of P. vivax-infected patients, but no P. falciparum-infected subjects, showed impaired maturation of circulating DCs, with low surface expression of CD86. Although vivax malaria patients overall had a less inflammatory cytokine response, with a higher interleukin-10 (IL-10)/tumor necrosis factor alpha (TNF-␣) ratio, this finding did not translate to milder clinical manifestations than those of falciparum malaria patients. We discuss the potential implications of these findings for species-specific pathogenesis and longlasting protective immunity to malaria.

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c + Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

“…In fact, an antimalarial compound with IDO-inhibitory properties was recently described (54). In this study, the plasma KT ratio and the plasma kynurenine concentration were strongly correlated with Treg activation, indirectly supporting an immune regulatory function of systemic IDO activity in vivax malaria, an infection in which Treg are known to be induced (11,14,55,56). However, it is not clear whether Treg contribute to the onset of disease by dampening or preventing the initiation of effector immune responses or whether they act to control immune-mediated pathology associated with malaria.…”

“…In clinical vivax malaria, mDC subsets and pDC decline (12,14), with one study reporting stable pDC numbers (11). However, no studies have reported mDC subset activation, and few studies have assessed total DC activation in clinical vivax malaria (11,12). In studies examining total DC, CD86 (11,12) and HLA-DR (12) expression were both significantly reduced.…”

“…However, no studies have reported mDC subset activation, and few studies have assessed total DC activation in clinical vivax malaria (11,12). In studies examining total DC, CD86 (11,12) and HLA-DR (12) expression were both significantly reduced. Complexities in MHC class II antigen-processing pathways provide multiple targets for pathogen interference, from modulation of de novo synthesis (36) to enhanced ubiquitination of existing MHC class II molecules (37).…”

“…Together, these reports suggest that, at least in a first infection, P. vivax and P. falciparum exert comparable effects on mDC subsets. In clinical vivax malaria, mDC subsets and pDC decline (12,14), with one study reporting stable pDC numbers (11). However, no studies have reported mDC subset activation, and few studies have assessed total DC activation in clinical vivax malaria (11,12).…”

“…In Plasmodium falciparum CHMI, we previously reported loss of total peripheral blood myeloid DC (mDC) and plasmacytoid DC (pDC) (9), as well as CD1c ϩ mDC dysfunction, characterized by impaired expression of major histocompatibility complex (MHC) class II and skewed proinflammatory cytokine production (10). In areas where malaria is endemic, there is no consensus as to whether P. vivax infection leads to stable pDC and mDC numbers (11), decreases pDC and mDC numbers (12,13), or differentially affects pDC and mDC numbers (14). In adults with patent or subpatent asymptomatic P. vivax infection, pDC and mDC numbers are retained (13,15).…”