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Thromb Haemost 2011; 106(02): 353-362
DOI: 10.1160/TH11-01-0020
Platelets and Blood Cells
Schattauer GmbH

Platelets regulate CD4+ T-cell differentiation via multiple chemokines in humans

Norbert Gerdes   *
1   Experimental Cardiovascular Research Unit at the Center for Molecular Medicine - Solna, Karolinska Institute, Stockholm, Sweden
4   Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
,
Linjing Zhu   *
2   Clinical Pharmacology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
3   Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
,
Maria Ersoy
2   Clinical Pharmacology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
,
Andreas Hermansson
1   Experimental Cardiovascular Research Unit at the Center for Molecular Medicine - Solna, Karolinska Institute, Stockholm, Sweden
,
Paul Hjemdahl
2   Clinical Pharmacology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
,
Hu Hu
3   Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
,
Göran K. Hansson
1   Experimental Cardiovascular Research Unit at the Center for Molecular Medicine - Solna, Karolinska Institute, Stockholm, Sweden
,
Nailin Li
2   Clinical Pharmacology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
› Author Affiliations Financial support: This work was supported by grants from the Swedish Research Council, the Swedish Heart-Lung Foundation, the Karolinska Institute, the Swedish Society of Medicine, and the Stockholm County Council.
Further Information

Publication History

Received: 16 January 2011

Accepted after major revision: 12 May 2011

Publication Date:
25 November 2017 (online)

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Summary

Atherosclerosis is an inflammatory and thrombotic disease. Both platelets and lymphocytes play important roles in atherogenesis. However, information on their interaction is limited. We therefore studied how platelets regulate CD4+ T cell activation and differentiation. Human CD4+ T cells and autologous platelets were co-cultured. Platelets concentration-dependently enhanced anti-CD3/CD28-induced IFNγ production by CD4+ T cells, but attenuated their proliferation. Abrogation of heterotypic cell-cell contact partially reversed the enhancement, and supernatant from activated platelets partially mimicked the enhancement, suggesting that platelets exert their effects via both soluble mediators and direct cell-cell contact. Platelets enhanced the production of IL-10 and cytokines characteristic for type 1 T helper (TH1) (IFNγ/ TNFα) and TH17 (IL-17) cells, but influenced TH2 cytokines (IL-4/IL-5) little. The cytokine responses were accompanied by enhanced TH1/TH17/TReg differentiation. Using neutralising antibodies and recombinant PF4, RANTES, and TGFβ, we found that platelet-derived PF4 and RANTES enhanced both pro- and anti-inflammatory cytokine production, whilst recombinant TGFβ enhanced IL-10 but not TNFα production. In conclusion, platelets enhance the differentiation and cytokine production of anti-CD3/CD28-stimulated CD4+ T cells via both multiple chemokines and direct cell-cell contact. Our study provides new insights into the cross-talk between thrombosis and adaptive immunity, and indicates that platelets can enhance T-effector cell development.

Keywords

Platelets - CD4+ T cells - regulatory T cells - TH17 cells - adaptive immunity

* These authors contributed equally to the study.


 

  • References

  • 1 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
    CrossrefPubMedSearch in Google Scholar
  • 2 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
    CrossrefPubMedSearch in Google Scholar
  • 3 Lievens D, Eijgelaar WJ, Biessen EA. et al. The multi-functionality of CD40L and its receptor CD40 in atherosclerosis. Thromb Haemost 2009; 102: 206-214.
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 2009; 102: 248-257.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Zhou X, Nicoletti A, Elhage R. et al. Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 2000; 102: 2919-2922.
    CrossrefPubMedSearch in Google Scholar
  • 6 Ait-Oufella H, Salomon BL, Potteaux S. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006; 12: 178-180.
    CrossrefPubMedSearch in Google Scholar
  • 7 Huo Y, Schober A, Forlow SB. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 9: 61-67.
    CrossrefPubMedSearch in Google Scholar
  • 8 Massberg S, Brand K, Gruner S. et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: 887-896.
    CrossrefPubMedSearch in Google Scholar
  • 9 Gawaz M, Stellos K, Langer HF. Platelets modulate atherogenesis and progression of atherosclerotic plaques via interaction with progenitor and dendritic cells. J Thromb Haemost 2008; 6: 235-242.
    CrossrefPubMedSearch in Google Scholar
  • 10 Langer HF, Gawaz M. Platelet-vessel wall interactions in atherosclerotic disease. Thromb Haemost 2008; 99: 480-486.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Li N. Platelet lymphocyte cross-talk. J Leukoc Biol 2008; 83: 1069-1078.
    CrossrefPubMedSearch in Google Scholar
  • 12 Pitchford SC, Momi S, Giannini S. et al. Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation. Blood 2005; 105: 2074-2081.
    CrossrefPubMedSearch in Google Scholar
  • 13 Li N, Ji Q, Hjemdahl P. Platelet-lymphocyte conjugation differs between lymphocyte subpopulations. J Thromb Haemost 2006; 4: 874-881.
    CrossrefPubMedSearch in Google Scholar
  • 14 Diacovo TG, Puri KD, Warnock RA. et al. Platelet-mediated lymphocyte delivery to high endothelial venules. Science 1996; 273: 252-255.
    CrossrefPubMedSearch in Google Scholar
  • 15 Hu H, Zhu L, Huang Z. et al. Platelets enhance lymphocyte adhesion and infiltration into arterial thrombus. Thromb Haemost 2010; 104: 1184-1192.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Elzey BD, Tian J, Jensen RJ. et al. Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity 2003; 19: 9-19.
    CrossrefPubMedSearch in Google Scholar
  • 17 Gregg EO, Yarwood L, Wagstaffe MJ. et al. Immunomodulatory properties of platelet factor 4: prevention of concanavalin A suppressor-induction in vitro and augmentation of an antigen-specific delayed-type hypersensitivity response in vivo. Immunology 1990; 70: 230-234.
    PubMedSearch in Google Scholar
  • 18 Liu CY, Battaglia M, Lee SH. et al. Platelet factor 4 differentially modulates CD4+CD25+ (regulatory) versus CD4+CD25- (nonregulatory) T cells. J Immunol 2005; 174: 2680-2686.
    CrossrefPubMedSearch in Google Scholar
  • 19 Hansson GK, Libby P, Schonbeck U. et al. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002; 91: 281-291.
    CrossrefPubMedSearch in Google Scholar
  • 20 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.
    CrossrefPubMedSearch in Google Scholar
  • 21 Lambert MP, Rauova L, Bailey M. et al. Platelet factor 4 is a negative autocrine in vivo regulator of megakaryopoiesis: clinical and therapeutic implications. Blood 2007; 110: 1153-1160.
    CrossrefPubMedSearch in Google Scholar
  • 22 Koenen RR, von Hundelshausen P, Nesmelova IV. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 2009; 15: 97-103.
    CrossrefPubMedSearch in Google Scholar
  • 23 Li N, Hu H, Lindqvist M. et al. Platelet-leukocyte cross talk in whole blood. Arterioscl Thromb Vasc Biol 2000; 20: 2702-2708.
    CrossrefPubMedSearch in Google Scholar
  • 24 Hu H, Zhang W, Li N. Glycoprotein IIb/IIIa inhibition attenuates platelet-activating factor-induced platelet activation by reducing protein kinase C activity. J Thromb Haemost 2003; 1: 1805-1812.
    CrossrefPubMedSearch in Google Scholar
  • 25 Weber C. Platelets and chemokines in atherosclerosis: partners in crime. Circ Res 2005; 96: 612-616.
    CrossrefPubMedSearch in Google Scholar
  • 26 Zernecke A, Shagdarsuren E, Weber C. Chemokines in atherosclerosis: an update. Arterioscler Thromb Vasc Biol 2008; 28: 1897-1908.
    CrossrefPubMedSearch in Google Scholar
  • 27 Koenen RR, Weber C. Therapeutic targeting of chemokine interactions in atherosclerosis. Nat Rev Drug Discov 2010; 9: 141-153.
    CrossrefPubMedSearch in Google Scholar
  • 28 Sachais BS, Turrentine T, Dawicki Mc, Kenna JM. et al. Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE-/- mice. Thromb Haemost 2007; 98: 1108-1113.
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Robertson AK, Rudling M, Zhou X. et al. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest 2003; 112: 1342-1350.
    CrossrefPubMedSearch in Google Scholar
  • 30 Zhou L, Lopes JE, Chong MM. et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008; 453: 236-240.
    CrossrefPubMedSearch in Google Scholar
  • 31 Potteaux S, Combadiere C, Esposito B. et al. Role of bone marrow-derived CC-chemokine receptor 5 in the development of atherosclerosis of low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol 2006; 26: 1858-1863.
    CrossrefPubMedSearch in Google Scholar
  • 32 Zernecke A, Liehn EA, Gao JL. et al. Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10. Blood 2006; 107: 4240-4243.
    CrossrefPubMedSearch in Google Scholar