Ectosomes released by platelets induce differentiation of CD4+ T cells into T regulatory cells

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 IFN gamma, TNF alpha and IL-6, and increased the production of TGF-beta 1. Concomitantly, PLT-Ecto-exposed CD4(+) T cells displayed increased frequencies of CD25(high) 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 naive T cells into Foxp3(+) cells, but had no effect on predifferentiated Foxp3(+) regulatory T cells (Tregs). Importantly, PLT-Ectoinduced 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-beta 1, as they were to some extent inhibited by PLT-Ecto pretreatment with TGF-beta 1-neutralising antibodies. Interestingly, ectosome-derived TGF-beta 1 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.