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

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 IFN gamma 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 (T(H)1) (IFN gamma/TNF alpha) and T(H)17 (IL-17) cells, but influenced T(H)2 cytokines (IL-4/IL-5) little. The cytokine responses were accompanied by enhanced T(H)1/T(H)17/T-Reg differentiation. Using neutralising antibodies and recombinant PF4, RANTES, and TGF beta, we found that platelet-derived PF4 and RANTES enhanced both pro- and anti-inflammatory cytokine production, whilst recombinant TGF beta enhanced IL-10 but not TNF alpha 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.