title: Ectosomes released by platelets induce differentiation of CD4+T cells into T regulatory cells.
abstract: Accumulating evidence suggests an immune-modulatory role for platelets (PLT) and PLT-derived microvesicles. In particular, ectosomes, i.e. vesicles budding from PLT surface, have been shown to exert immunosuppressive activities on phagocytes. Here we investigated the effects mediated by PLT-derived ectosomes (PLT-Ecto) on CD4+ T cells. Exposure of activated CD4+ T cells to PLT-Ecto decreased their release of IFNγ, TNFα and IL-6, and increased the production of TGF-β1. Concomitantly, PLT-Ecto-exposed CD4+ T cells displayed increased frequencies of CD25high Foxp3+ cells. These phenomena were dose-dependent and PLT-Ecto specific, since they were not observed in the presence of polymorphonuclear- and erythrocyte-derived ectosomes. Analysis of specific T cell subsets revealed that PLT-Ecto induced differentiation of naïve T cells into Foxp3+ cells, but had no effect on pre-differentiated Foxp3+ regulatory T cells (Tregs). Importantly, PLT-Ecto-induced Foxp3+ cells were as effective as peripheral blood Tregs in suppressing CD8+ T cell proliferation. PLT-Ecto-mediated effects were partly dependent on PLT-derived TGF-β1, as they were to some extent inhibited by PLT-Ecto pretreatment with TGF-β1-neutralising antibodies. Interestingly, ectosome-derived TGF-β1 levels correlated with Foxp3+ T cell frequencies in blood of healthy donors. In conclusion, PLT-Ecto induce differentiation of CD4+ T cells towards functional Tregs. This may represent a mechanism by which PLT-Ecto enhance peripheral tolerance.
authors.affiliation: Salima Sadallah, Immunonephrology Laboratory, Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland, Tel.: +41 61 265 32 62, Fax: +41 61 265 23 50, E-mail: salima.sadallah@unibas.ch.
authors.forename: S
authors.initials: S
authors.lastname: Sadallah
authors.forename: F
authors.initials: F
authors.lastname: Amicarella
authors.forename: C
authors.initials: C
authors.lastname: Eken
authors.forename: G
authors.initials: G
authors.lastname: Iezzi
authors.forename: J A
authors.initials: JA
authors.lastname: Schifferli
mesh_terms: D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes; D002454:Cell Differentiation; D049109:Cell Proliferation; D055252:Cell-Derived Microparticles / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D019899:Paracrine Communication; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C573415:IFNG protein, human; C508017:IL2RA protein, human; C508600:IL6 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Microparticles; T cell differentiation; ectosomes; extracellular vesicles; platelet immunology