T cell-mediated inflammatory immune responses contribute to both the clearance and pathology of malaria infections; the host's ability to down-regulate inflammation once parasitemia is controlled is crucial to avoid immune-mediated pathology but remains poorly understood. Various regulatory populations of T lymphocytes can modulate inflammatory immune responses and there has been considerable recent interest in the potential for regulatory T cells to modify the outcome of both murine and human malaria infections. Here, we review these studies, focussing in particular on recent studies in humans, propose a model by which different regulatory T cell populations might contribute to the control of inflammation at different stages of infection and discuss the implications for the design of safe and effective malaria vaccines.
"Regulatory T cells (Tregs) can suppress both protective as well as pathological adaptive immune responses, and are elevated in both human falciparum and vivax malaria as well as in murine malaria models (Scholzen et al., 2010). Although the consequences of elevated Treg levels during malaria are yet to be determined, several studies indicate that depending on the stage of infection, increased Treg levels can be protective or detrimental to the host (Finney et al., 2010; Hansen and Schofield, 2010; Scholzen et al., 2010). In addition to potentially limiting responses to parasite antigens (Ho et al., 1986; Bejon et al., 2007), elevated Treg levels during acute blood-stage malaria infection might also contribute to the reduced acquisition of immune responses to heterologous antigens, such as standard childhood vaccines (Greenwood et al., 1972; Williamson and Greenwood, 1978; Whittle et al., 1984). "
[Show abstract][Hide abstract] ABSTRACT: Elevated levels of regulatory T cells following Plasmodium infection are a well-reported phenomenon that can influence both protective and pathological anti-parasite responses, and might additionally impact on vaccine responses in acutely malaria infected individuals. The mechanisms underlying their induction or expansion by the parasite, however, are incompletely understood. In a previous study, Plasmodium falciparum infected red blood cells (iRBCs) were shown to induce effector-cytokine producing Foxp3int CD4+ T cells, as well as regulatory Foxp3hi CD4+ T cells in vitro. The aim of the present study was to determine the contribution of parasite components to the induction of Foxp3 expression in human CD4+ T cells. Using the surface PfEMP1-deficient parasite line 1G8, we demonstrate that induction of Foxp3hi and Foxp3int CD4+ T cells is independent of PfEMP1 expression on iRBCs. We further demonstrate that integrity of iRBCs is no requirement for the induction of Foxp3 expression. Finally, transwell experiments showed that induction of Foxp3 expression, and specifically the generation of Foxp3hi as opposed to Foxp3int CD4 T cells, can be mediated by soluble parasite components smaller than 20 nm and thus likely distinct from the malaria pigment hemozoin. These results suggest that the induction of Foxp3hi T cells by P. falciparum is largely independent of two key immune modulatory parasite components, and warrant future studies into the nature of the Foxp3hi inducing parasite components to potentially allow their exclusion from vaccine formulations.
Frontiers in Microbiology 05/2014; 5:200. DOI:10.3389/fmicb.2014.00200 · 3.99 Impact Factor
"1988). IL-2 might regulate the balance between effector Th1 cells and Treg cells during blood-stage malaria (Finney et al. 2010; Scholzen et al. 2010; Berretta et al. 2011). All together, PvMSP-10 induced Th1 profile predominant response in mouse suggesting that PvMSP10 might be able to produce an effective protection for host. "
[Show abstract][Hide abstract] ABSTRACT: Among the proteins involved in the invasion by merozoite, the glycosylphosphatidylinositol-anchored proteins (GPI-APs) are suggested as potential vaccine candidates because of their localization to apical organelles and the surface; these candidates are predicted to play essential roles during invasion. As a GPI-AP, Plasmodium vivax merozoite surface protein 10 (PvMSP-10) induces high antibody titers. However, such high antibody titers have shown no protective efficacy for animals challenged with P. vivax parasites in a previous study. To adequately evaluate the immunogenicity and further characterize PvMSP-10 in order to understand its vaccine potential, we assessed its immunogenicity by immunizing BALB/c mice with cell-free expressed recombinant PvMSP-10 protein. The antigenicity of MSP-10 was analyzed, and we found 42 % sensitivity and 95 % specificity using serum samples from P. vivax-infected Korean patients. The IgG1 and IgG3 were the predominant immunoreactive antibodies against PvMSP-10 in vivax patient sera, and IgG1 and IgG3 and Th1-type cytokines were predominantly secreted in PvMSP-10-immunized mice. We conclude that the immunogenicity and antigenicity of MSP-10 may serve as a potential vaccine against vivax malaria.
Parasitology Research 04/2014; 113(7). DOI:10.1007/s00436-014-3907-8 · 2.10 Impact Factor
"If the expansion of Tregs takes place in the initial phase of infection, it may hamper the inflammatory response required for clearance of infected red cells from circulation, increasing the risk that uncontrolled parasite growth could lead to severe disease. If Tregs are activated later in infection, however, once parasitaemia has been brought under control, they may prevent the onset of severe immune-mediated pathology (Finney et al., 2010).c mi_1622 1328..1338 The mechanisms that mobilize and activate Tregs during a malaria infection are not completely defined. "
[Show abstract][Hide abstract] ABSTRACT: Increased numbers of T regulatory cells (Tregs), key mediators of immune homeostasis, were reported in human and murine malaria and it is current opinion that these cells play a role in balancing protective immunity and pathogenesis during infection. However, the mechanisms governing their expansion during malaria infection are not completely defined. In this article we show that soluble extracts of Plasmodium falciparum (PfSEs), but not equivalent preparation of uninfected erythrocytes, induce the differentiation of polyclonally activated CD4(+) cells in Tregs endowed with strong suppressive activity. PfSEs activate latent TGFβ bound on the membrane of Treg cells, thus allowing the cytokine interaction with TGFβ receptor, and inducing Foxp3 gene expression and TGFβ production. The activation of membrane-bound latent TGFβ by PfSEs is significantly reduced by a broad-spectrum metalloproteinases inhibitor with Zn(++) -chelating activity, and completely inhibited by the combined action of such inhibitor and antibodies to a P. falciparum thrombospondin-related adhesive protein (PfTRAP). We conclude that Pf-Zn(++) -dependent proteinases and, to a lesser extent, PfTRAP molecules are involved in the activation of latent TGFβ bound on the membrane of activated Treg cells and suggest that, in malaria infection, this mechanism could contribute to the expansion of Tregs with different antigen specificity.
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