Modulation of the Immune and Inflammatory Responses by Plasmodium falciparum Schizont Extracts: Role of Myeloid Dendritic Cells in Effector and Regulatory Functions of CD4 ⁺ Lymphocytes

Abstract

eThe optimal immune response to malaria infection comprises rapid induction of inflammatory responses promptly counteracted by regulatory mechanisms to prevent immunopathology. To evaluate the role of dendritic cells (DC) in the balance of parasite-induced inflammatory/anti-inflammatory mechanisms, we studied the activity of monocyte-derived dendritic cells (MDDC), previously exposed to soluble extracts of Plasmodium falciparum-infected red blood cells (PfSE), in the differentiation of CD4 cells isolated from donors never exposed to malaria infection. We show that MDDC exposed to PfSE are extremely efficient to induce a contemporary differentiation of TH1 effector cells and T regulatory (Treg) cells in CD4 T cells even when exposed to low concentrations of parasitic extracts. Treg cells induced by MDDC infected with PfSE (MDDC-PfSE) produce transforming growth factor beta (TGF-␤) and interleukin 10 (IL-10) and are endowed with strong suppressive properties. They also show phenotypical and functional peculiarities, such as the contemporary expression of markers of Treg and TH1 differentiation and higher sensitivity to TLR4 ligands both inducing an increasing production of suppressive cytokines. On the whole, our data indicate that MDDC exposed to PfSE orchestrate a well-balanced immune response with timely differentiation of TH1 and Treg cells in CD4 cells from nonimmune donors and suggest that, during the infection, the role of MDCC could be particularly relevant in low-parasitemia conditions.

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

“…TGF-b plays a key role in maintaining the balance between immunoprotection mediated by T cells and immunopathology either in experimental models of malaria and toxoplasma infection and in human diseases [5,29,30]. Macrophages and dendritic cells mostly account for TGF-b production following parasite uptake; nevertheless, the production of these cytokines by activated CD4 þ T cells following a direct stimulation with parasites or parasite products has also been reported [10,11,15]. Our data show that the synthesis of IL10 by CD4 þ T lymphocytes is significantly induced only by P. falciparum extracts according to our previous report [10]; indeed the production of TGF-b is induced also by T. gondii and by L. infantum extracts.…”

“…Heatinactivated parasitic extracts (HIPE) or medium alone were used as "negative" controls while P. falciparum extracts at 10 mg/ml was used as positive control [15]. We chose to quantify the expansion of CD25 high Foxp3 þ Treg populations in cells activated by anti-CD3/CD28 antibodies after 5 days of culture, because at this time the effects of TCR-activation on the expression of Foxp3 gene by CD4 þ T lymphocytes are not evident ( [25,26], our data in Fig.…”

“…Indeed in some parasitic infections, a high production of TGF-b and IL-10 by activated T cells has been reported even in absence of accessory cells [11,15]. Thus we studied the effect of parasitic extracts on the production of TGF-b and IL-10 by activated T lymphocytes.…”

“…TLR2 and TLR4 which recognize parasitic glycosylphosphatidylinositol anchors and glycoinositolphospholipids respectively are also expressed by activated T lymphocytes and are involved in T lymphocyte functions such as survival, IL2 production, TH1/TH17 shift and sensitivity to T regulatory [32,33]. We first investigated the possibility that culture in the presence of parasitic extracts could affect the expression of TLR2 and TLR4 as reported in different experimental systems [15]. As shown in Fig.…”

“…Activation of latent TGF-b on the surface of activated T cells is a requirement for triggering signals from TGF-b receptor which regulate the expression of Foxp3 gene, the master regulator of T regulatory cell function [17,18]. Either P. falciparum extracts or H. polygyrus excretory-secretory proteins were shown to be able to activate TGF-b receptor on the surface of activated lymphocytes [15,19]. The effects of live parasites or their soluble extracts on the modulation of immune responses are well defined and considered as possible tools for modulating the responses in autoimmune diseases [20].…”