title: Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin.
abstract: Self-tolerance and immune homeostasis are orchestrated by FOXP3(+)regulatory T cells (Tregs). Recent data have revealed that upon stimulation, Tregs may exhibit plasticity toward a proinflammatory phenotype, producing interleukin 17 (IL-17) and/or interferon γ (IFN-γ). Such deregulation of Tregs may contribute to the perpetuation of inflammatory processes, including graft-versus-host disease. Thus, it is important to identify immunomodulatory factors influencing Treg stability. Platelet-derived microparticles (PMPs) are involved in hemostasis and vascular health and have recently been shown to be intimately involved in (pathogenic) immune responses. Therefore, we investigated whether PMPs have the ability to affect Treg plasticity. PMPs were cocultured with healthy donor peripheral blood-derived Tregs that were stimulated with anti-CD3/CD28 monoclonal antibodies in the presence of IL-2, IL-15, and IL-1β. PMPs prevented the differentiation of peripheral blood-derived Tregs into IL-17- and IFN-γ-producing cells, even in the presence of the IL-17-driving proinflammatory cytokine IL-1β. The mechanism of action by which PMPs prevent Treg plasticity consisted of rapid and selective P-selectin-dependent binding of PMPs to a CCR6(+)HLA-DR(+)memory-like Treg subset and their ability to inhibit Treg proliferation, in part through CXCR3 engagement. The findings that ~8% of Tregs in the circulation of healthy individuals are CD41(+)P-selectin(+)and that distinct binding of patient plasma PMPs to Tregs was observed support in vivo relevance. These findings open the exciting possibility that PMPs actively regulate the immune response at sites of (vascular) inflammation, where they are known to accumulate and interact with leukocytes, consolidating the (vascular) healing process.
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology.
authors.forename: Sip
authors.initials: S
authors.lastname: Dinkla
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology.
authors.forename: Bram
authors.initials: B
authors.lastname: van Cranenbroek
authors.affiliation: Department of Internal Medicine, and.
authors.forename: Wouter A
authors.initials: WA
authors.lastname: van der Heijden
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology.
authors.forename: Xuehui
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands; and.
authors.forename: Rike
authors.initials: R
authors.lastname: Wallbrecher
authors.affiliation: Cardiovascular and Cell Sciences Research Institute, St George's, University of London, London, United Kingdom.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Dumitriu
authors.affiliation: Department of Internal Medicine, and.
authors.forename: André J
authors.initials: AJ
authors.lastname: van der Ven
authors.affiliation: Department of Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands; and.
authors.forename: Giel J C G M
authors.initials: GJ
authors.lastname: Bosman
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology.
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology.
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000473:pathology / Q000648:ultrastructure*; D002454:Cell Differentiation / Q000276:immunology; D055252:Cell-Derived Microparticles / Q000473:pathology* / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D038041:Lymphopoiesis / Q000502:physiology; D019007:P-Selectin / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000502:physiology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508717:IL17A protein, human; C508017:IL2RA protein, human; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D019007:P-Selectin; C546937:SELP protein, human