Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFβ-mediated signals

Abstract

Summary Increased numbers of T regulatory cells (Tregs),

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

“…According to previous report [10], Fig. 1, panel D shows that, in cells activated by anti-CD3/CD28 antibodies, the expression of Foxp3 gene is significantly higher after 72 h of culture compared to day 0.…”

“…Data obtained from cytofluorimetric analysis show that, among the parasites tested, only L. infantum extracts are able to expand the Treg population. This activity is dose-dependent and it is completely abolished by heat-treatment of extracts at 80 C. Previously we showed that, in the same experimental model, P. falciparum extracts expand a Treg population with CD25 high Foxp3 þ phenotype endowed with potent suppressive activity: the parasitic molecules responsible for Treg expansion activate the latent TGF-b complex either in soluble or membrane-bound form [10,16]; active TGF-b, through the interaction with TGF-b receptor expressed on the membrane of effector T cells, force their conversion to the T regulatory phenotype [10]. In this study we show that, similarly to P. falciparum extracts, also L. infantum extracts activate the TGF-b receptor pathway as assessed by the phosphorylation of SMAD 2/3, transcription factors involved in the regulation of Foxp3 gene expression [34].…”

“…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.…”

“…TGF-b was shown to be involved in the expansion of both native and induced Foxp3 þ Tregs in malaria [5e7], toxoplasmosis [8], and leishmaniasis [9]. Both TCR-dependent and independent mechanisms have been demonstrated to account for Treg expansion during parasitic infections [10,11]. In malaria infection accessory cells engulfed with parasites as well as activated T lymphocytes produce high amounts of TGF-b and IL-10 which might easily induce the conversion of bystander effector T cells to the regulatory phenotype [11].…”

Dendritic cells treated with crude Plasmodium berghei extracts acquire immune‐modulatory properties and suppress the development of autoimmune neuroinflammation

“…It was previously demonstrated that P. falciparum soluble extracts potentiate the induction and function of human regulatory T cells through a transforming growth factorb-dependent mechanism. 41 In Plasmodium chabaudi infection of mice, there is an increase in the frequency of peripheral Treg cells, which modifies the course of EAE. 42 Interestingly, DCs modulated with PbX presented different results when cultured with naive and encephalitogenic T cells regarding the secretion of IFN-c.…”