title: Platelets regulate CD4⁺ T-cell differentiation via multiple chemokines in humans.
abstract: 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.
authors.affiliation: Experimental Cardiovascular Research Unit at the Center for Molecular Medicine - Solna, Karolinska Institute, Stockholm, Sweden.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gerdes
authors.forename: Linjing
authors.initials: L
authors.lastname: Zhu
authors.forename: Maria
authors.initials: M
authors.lastname: Ersoy
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermansson
authors.forename: Paul
authors.initials: P
authors.lastname: Hjemdahl
authors.forename: Hu
authors.initials: H
authors.lastname: Hu
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Nailin
authors.initials: N
authors.lastname: Li
mesh_terms: D056704:Adaptive Immunity; D000328:Adult; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002450:Cell Communication; D002454:Cell Differentiation / Q000276:immunology; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors; D018925:Chemokines / Q000096:biosynthesis*; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000037:antagonists & inhibitors; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; C508609:IL10 protein, human; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D010978:Platelet Factor 4