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 TGFß bound on the membrane of Treg cells, thus allowing the cytokine interaction with TGFß receptor, and inducing Foxp3 gene expression and TGFß production. The activation of membrane-bound latent TGFß 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 TGFß 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.
Subject(s)
Plasmodium falciparum/immunology , Plasmodium falciparum/metabolism , Signal Transduction/physiology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/metabolism , Blotting, Western , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Dimethyl Sulfoxide/pharmacology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Humans , Protease Inhibitors/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Signal Transduction/genetics , T-Lymphocytes, Regulatory/drug effects , Transforming Growth Factor beta/geneticsABSTRACT
Previous interethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than are sympatric ethnic groups. This lower susceptibility is not associated to classic malaria-resistance genes, and the analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in Fulani. In the present study we compared the expression profile of a panel of genes involved in immune response in peripheral blood mononuclear cells (PBMC) from Fulani and sympatric Mossi from Burkina Faso. An increased expression of T helper 1 (TH1)-related genes (IL-18, IFNgamma, and TBX21) and TH2-related genes (IL-4 and GATA3) and a reduced expression of genes distinctive of T regulatory activity (CTLA4 and FOXP3) were observed in Fulani. Microarray analysis on RNA from CD4+ CD25+ (T regulatory) cells, performed with a panel of cDNA probes specific for 96 genes involved in immune modulation, indicated obvious differences between the two ethnic groups with 23% of genes, including TGFbeta, TGFbetaRs, CTLA4, and FOXP3, less expressed in Fulani compared with Mossi and European donors not exposed to malaria. As further indications of a low T regulatory cell activity, Fulani showed lower serum levels of TGFbeta and higher concentrations of the proinflammatory chemokines CXCL10 and CCL22 compared with Mossi; moreover, the proliferative response of Fulani to malaria antigens was not affected by the depletion of CD25+ regulatory cells whereas that of Mossi was significantly increased. The results suggest that the higher resistance to malaria of the Fulani could derive from a functional deficit of T regulatory cells.
