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Thromb Haemost 2014; 112(06): 1219-1229
DOI: 10.1160/th14-03-0281
Platelets and Blood Cells
Schattauer GmbH

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

Salima Sadallah   *
1   Department of Biomedicine, University Hospital Basel, Switzerland
,
Francesca Amicarella   *
2   Institute of Surgical Research and Department of Biomedicine, University Hospital Basel, Switzerland
,
Ceylan Eken
1   Department of Biomedicine, University Hospital Basel, Switzerland
,
Giandomenica Iezzi   +
2   Institute of Surgical Research and Department of Biomedicine, University Hospital Basel, Switzerland
,
Jürg A. Schifferli   +
1   Department of Biomedicine, University Hospital Basel, Switzerland
› Author Affiliations Financial support: This work was supported by the Swiss National Science Foundation (320030–146255/1).
Further Information

Publication History

Received: 27 March 2014

Accepted after major revision: 14 August 2014

Publication Date:
18 November 2017 (online)

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Summary

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 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-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.

Keywords

Microparticles - ectosomes - extracellular vesicles - platelet immunology - T cell differentiation

* These authors contributed equally as first authors of the manuscript.


+ These authors contributed equally as senior authors of the manuscript.


 

  • References

  • 1 Stroncek DF, Rebulla P. Platelet transfusions. Lancet 2007; 370: 427-438.
    CrossrefPubMedGoogle Scholar
  • 2 Vamvakas EC. Platelet transfusion and adverse outcomes. Lancet 2004; 364: 1736-1738.
    CrossrefPubMedGoogle Scholar
  • 3 Shrivastava M. The platelet storage lesion. Transfus Apher Sci 2009; 41: 105-113.
    CrossrefPubMedGoogle Scholar
  • 4 Thon JN, Schubert P, Devine DV. Platelet storage lesion: a new understanding from a proteomic perspective. Transfus Med Rev 2008; 22: 268-279.
    CrossrefPubMedGoogle Scholar
  • 5 von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007; 100: 27-40.
    CrossrefPubMedGoogle Scholar
  • 6 Sinauridze EI, Kireev DA, Popenko NY. et al. Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 2007; 97: 425-434.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Morel O, Morel N, Jesel L. et al. Microparticles: a critical component in the nexus between inflammation, immunity, and thrombosis. Semin Immunopathol 2011; 33: 469-486.
    CrossrefPubMedGoogle Scholar
  • 8 Heijnen HF, Schiel AE, Fijnheer R. et al. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 1999; 94: 3791-3799.
    PubMedGoogle Scholar
  • 9 Sadallah S, Eken C, Martin PJ. et al. Microparticles (ectosomes) shed by stored human platelets downregulate macrophages and modify the development of dendritic cells. J Immunol 2011; 186: 6543-6552.
    CrossrefPubMedGoogle Scholar
  • 10 Rank A, Nieuwland R, Crispin A. et al. Clearance of platelet microparticles in vivo. Platelets 2011; 22: 111-116.
    CrossrefPubMedGoogle Scholar
  • 11 van der Pol E, Boing AN, Harrison P. et al. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev 2012; 64: 676-705.
    CrossrefPubMedGoogle Scholar
  • 12 Gasser O, Schifferli JA. Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood 2004; 104: 2543-2548.
    CrossrefPubMedGoogle Scholar
  • 13 Eken C, Gasser O, Zenhaeusern G. et al. Polymorphonuclear neutrophil-derived ectosomes interfere with the maturation of monocyte-derived dendritic cells. J Immunol 2008; 180: 817-824.
    CrossrefPubMedGoogle Scholar
  • 14 Sadallah S, Eken C, Schifferli JA. Erythrocyte-derived ectosomes have immunosuppressive properties. J Leukoc Biol 2008; 84: 1316-1325.
    CrossrefPubMedGoogle Scholar
  • 15 Chen X, Doffek K, Sugg SL. et al. Phosphatidylserine regulates the maturation of human dendritic cells. J Immunol 2004; 173: 2985-2994.
    CrossrefPubMedGoogle Scholar
  • 16 Wu Y, Tibrewal N, Birge RB. Phosphatidylserine recognition by phagocytes: a view to a kill. Trends Cell Biol 2006; 16: 189-197.
    CrossrefPubMedGoogle Scholar
  • 17 Shi D, Fu M, Fan P. et al. Artificial phosphatidylserine liposome mimics apoptotic cells in inhibiting maturation and immunostimulatory function of murine myeloid dendritic cells in response to 1-chloro-2,4-dinitrobenze in vitro. Arch Dermatol Res 2007; 299: 327-336.
    CrossrefPubMedGoogle Scholar
  • 18 Pap E, Pallinger E, Falus A. The role of membrane vesicles in tumorigenesis. Crit Rev Oncol Hematol 2011; 79: 213-223.
    CrossrefPubMedGoogle Scholar
  • 19 de Almeida MC, Silva AC, Barral A. et al. A simple method for human peripheral blood monocyte isolation. Mem Inst Oswaldo Cruz 2000; 95 (02) 221-3.
    CrossrefPubMedGoogle Scholar
  • 20 Hess C, Sadallah S, Hefti A. et al. Ectosomes released by human neutrophils are specialized functional units. J Immunol 1999; 163: 4564-4573.
    PubMedGoogle Scholar
  • 21 Gasser O, Hess C, Miot S. et al. Characterisation and properties of ectosomes released by human polymorphonuclear neutrophils. Exp Cell Res 2003; 285: 243-257.
    CrossrefPubMedGoogle Scholar
  • 22 Rosenthal R, Groeper C, Bracci L. et al. Differential responsiveness to IL-2, IL-7, and IL-15 common receptor gamma chain cytokines by antigen-specific peripheral blood naive or memory cytotoxic CD8+ T cells from healthy donors and melanoma patients. J Immunother 2009; 32: 252-261.
    CrossrefPubMedGoogle Scholar
  • 23 Vasina EM, Cauwenberghs S, Staudt M. et al. Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release. Am J Blood Res 2013; 03: 107-123.
    PubMedGoogle Scholar
  • 24 Hunter MP, Ismail N, Zhang X. et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One 2008; 03: e3694.
    CrossrefPubMedGoogle Scholar
  • 25 Bode AP, Orton SM, Frye MJ. et al. Vesiculation of platelets during in vitro aging. Blood 1991; 77: 887-895.
    PubMedGoogle Scholar
  • 26 Chen W, Jin W, Hardegen N. et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198: 1875-1886.
    CrossrefPubMedGoogle Scholar
  • 27 Fantini MC, Becker C, Monteleone G. et al. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 2004; 172: 5149-5153.
    CrossrefPubMedGoogle Scholar
  • 28 Dons EM, Raimondi G, Cooper DK. et al. Induced regulatory T cells: mechanisms of conversion and suppressive potential. Hum Immunol 2012; 73: 328-334.
    CrossrefPubMedGoogle Scholar
  • 29 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-1061.
    CrossrefPubMedGoogle Scholar
  • 30 Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 2007; 110: 2983-2990.
    CrossrefPubMedGoogle Scholar
  • 31 Vercoulen Y, Wehrens EJ, van Teijlingen NH. et al. Human regulatory T cell suppressive function is independent of apoptosis induction in activated effector T cells. PLoS One 2009; 04: e7183.
    CrossrefPubMedGoogle Scholar
  • 32 Fleischer J, Grage-Griebenow E, Kasper B. et al. Platelet factor 4 inhibits proliferation and cytokine release of activated human T cells. J Immunol 2002; 169: 770-777.
    CrossrefPubMedGoogle Scholar
  • 33 Lei J, Hasegawa H, Matsumoto T. et al. Peroxisome proliferator-activated receptor alpha and gamma agonists together with TGF-beta convert human CD4+CD25- T cells into functional Foxp3+ regulatory T cells. J Immunol 2010; 185: 7186-7198.
    CrossrefPubMedGoogle Scholar
  • 34 Barry OP, Pratico D, Lawson JA. et al. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J Clin Invest 1997; 99: 2118-2127.
    CrossrefPubMedGoogle Scholar
  • 35 Italiano Jr. JE, Mairuhu AT, Flaumenhaft R. Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol 2010; 17: 578-584.
    CrossrefPubMedGoogle Scholar
  • 36 Flaumenhaft R, Mairuhu AT, Italiano JE. Platelet- and megakaryocyte-derived microparticles. Semin Thromb Hemost 2010; 36: 881-887.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Boilard E, Nigrovic PA, Larabee K. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583.
    CrossrefPubMedGoogle Scholar
  • 38 Boilard E, Blanco P, Nigrovic PA. Platelets: active players in the pathogenesis of arthritis and SLE. Nature Rev Rheumatol 2012; 08: 534-542.
    CrossrefPubMedGoogle Scholar
  • 39 Gerdes N, Zhu L, Ersoy M. et al. Platelets regulate CD4(+) T-cell differentiation via multiple chemokines in humans. Thromb Haemost 2011; 106: 353-362.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Li N. CD4+ T cells in atherosclerosis: regulation by platelets. Thromb Haemost 2013; 109: 980-990.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Kunder CA, St John AL, Li G. et al. Mast cell-derived particles deliver peripheral signals to remote lymph nodes. J Exp Med 2009; 206: 2455-2467.
    CrossrefPubMedGoogle Scholar