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

Annmaria Clemente, Roberto Caporale, Anna Rosa Sannella, Giancarlo Majori, Carlo Severini, Giulia Fadigati, Domenico Cirelli, Paolo Bonini, Enrico Garaci, Federico Cozzolino, Maria Gabriella Torcia

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1328-1338
Number of pages11
JournalCellular Microbiology
Volume13
Issue number9
DOIs
Publication statusPublished - Sep 2011

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Virology

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    Clemente, A., Caporale, R., Sannella, A. R., Majori, G., Severini, C., Fadigati, G., Cirelli, D., Bonini, P., Garaci, E., Cozzolino, F., & Torcia, M. G. (2011). Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFβ-mediated signals. Cellular Microbiology, 13(9), 1328-1338. https://doi.org/10.1111/j.1462-5822.2011.01622.x