Platelets Play Differential Role During the Initiation and Progression of Autoimmune Neuroinflammation

Circ Res. 2015 Oct 9;117(9):779-92. doi: 10.1161/CIRCRESAHA.115.306847. Epub 2015 Aug 20.


Rationale: Platelets are known to participate in vascular pathologies; however, their role in neuroinflammatory diseases, such as multiple sclerosis (MS), is unknown. Autoimmune CD4 T cells have been the main focus of studies of MS, although the factors that regulate T-cell differentiation toward pathogenic T helper-1/T helper-17 phenotypes are not completely understood.

Objective: We investigated the role of platelets in the modulation of CD4 T-cell functions in patients with MS and in mice with experimental autoimmune encephalitis, an animal model for MS.

Methods and results: We found that early in MS and experimental autoimmune encephalitis, platelets degranulated and produced soluble factors serotonin (5-hydroxytryptamine), platelet factor 4, and platelet-activating factor, which specifically stimulated differentiation of T cells toward pathogenic T helper-1, T helper-17, and interferon-γ/interleukin-17-producing CD4 T cells. At the later stages of MS and experimental autoimmune encephalitis, platelets became exhausted in their ability to produce proinflammatory factors and stimulate CD4 T cells but substantially increased their ability to form aggregates with CD4 T cells. Formation of platelet-CD4 T-cell aggregates involved the interaction of CD62P on activated platelets with adhesion molecule CD166 on activated CD4 T cells, contributing to downmodulation of CD4 T-cell activation, proliferation, and production of interferon-γ. Blocking of formation of platelet-CD4 T-cell aggregates during progression of experimental autoimmune encephalitis substantially enhanced proliferation of CD4 T cells in the central nervous system and the periphery leading to exacerbation of the disease.

Conclusion: Our study indicates differential roles for platelets in the regulation of functions of pathogenic CD4 T cells during initiation and progression of central nervous system autoimmune inflammation.

Keywords: T-lymphocytes; blood platelets; helper-inducer; interleukin-17; multiple sclerosis; serotonin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blood Platelets / immunology*
  • Blood Platelets / metabolism
  • Blood Platelets / ultrastructure
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / ultrastructure
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Coculture Techniques
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Female
  • Flow Cytometry
  • Humans
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Electron, Scanning
  • Middle Aged
  • Multiple Sclerosis / immunology*
  • Platelet Activating Factor / immunology
  • Platelet Activating Factor / metabolism
  • Platelet Factor 4 / immunology
  • Platelet Factor 4 / metabolism
  • Serotonin / immunology
  • Serotonin / metabolism


  • Interleukin-17
  • Platelet Activating Factor
  • Serotonin
  • Platelet Factor 4
  • Interferon-gamma