title: Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFβ-mediated signals.
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.
authors.affiliation: Department of Clinical Physiopathology, University of Firenze, Firenze, Italy.
authors.forename: AnnMaria
authors.initials: A
authors.lastname: Clemente
authors.forename: Roberto
authors.initials: R
authors.lastname: Caporale
authors.forename: Anna Rosa
authors.initials: AR
authors.lastname: Sannella
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Majori
authors.forename: Carlo
authors.initials: C
authors.lastname: Severini
authors.forename: Giulia
authors.initials: G
authors.lastname: Fadigati
authors.forename: Domenico
authors.initials: D
authors.lastname: Cirelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonini
authors.forename: Enrico
authors.initials: E
authors.lastname: Garaci
authors.forename: Federico
authors.initials: F
authors.lastname: Cozzolino
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Torcia
mesh_terms: D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010963:Plasmodium falciparum / Q000276:immunology* / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011480:Protease Inhibitors; D016212:Transforming Growth Factor beta; D004121:Dimethyl Sulfoxide