Platelets Play Differential Role During the Initiation and Progression of Autoimmune Neuroinflammation
Rationale: Platelets are known to participate in vascular pathologies; however, their role in neuroinflammatory diseases such as multiples 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 towards pathogenic Th1/Th17 phenotypes are not completely understood.
Objective: We investigated the role of platelets in the modulation of CD4 T cell functions in MS patients and in mice with experimental autoimmune encephalitis (EAE), an animal model for MS.
Methods and Results: We found that early in MS and EAE platelets degranulated and produced a number of soluble factors serotonin (5HT), PF4 and PAF, which specifically stimulated differentiation of T cells towards pathogenic Th1, Th17 and IFN-γ/IL-17-producing CD4 T cells. At the later stages of MS and EAE 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 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 IFN-γ. Blocking of formation of platelet-CD4 T cell aggregates during progression of EAE substantially enhanced proliferation of CD4 T cell in the CNS and the periphery leading to exacerbation of the disease.
Conclusions: Our study indicates differential roles for platelets in the regulation of functions of pathogenic CD4 T cells during initiation and progression of CNS autoimmune inflammation.
- Received May 18, 2015.
- Revision received August 18, 2015.
- Accepted August 20, 2015.