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Platelets regulate responses of type 1 T helper (Th1), Th17, and regulatory T (Treg) cells. However, little is known about how platelets influence the dynamics of CD4+ T-cell responses.To investigate the dynamics of platelet-regulated CD4+ T-cell activation and cross-talk and their underlying mechanisms.Human CD3/CD28-challenged CD4+ T cells were cultured without or with autologous platelets. Th1, Th17, and Treg responses were monitored during 5 days. Platelets simultaneously enhanced activation of Th1, Th17, and Treg cells within 48-h coculture. Thereafter, platelets remained augmentative for Treg but turned suppressive for Th1/Th17 responses. Without platelets, FoxP3 blockade inhibited Treg activation, which subsequently enhanced Th1 activation. In platelet–T-cell cocultures, however, FoxP3 blockade had no effect on Treg or Th1 activation. Neutralization of platelet-derived transforming growth factor β, but not Treg-derived interleukin-10, enhanced Th1 activation. These data suggest that Treg cells have limited impact on, while platelets are the primary regulator for Th1 suppression during the second phase of coculture. Combining carboxyfluorescein succinimidyl ester and FoxP3 staining, platelets were found to enhance Treg response by promoting cell proliferation of FoxP3+ T cells and to induce the suppression phrase of Th1 responses by inhibiting FoxP3− T-cell proliferation. The latter was markedly attenuated by TGFβ neutralization.Platelets constantly promote Treg cell response but exert a biphasic regulation on Th1/Th17 activation, namely a transient enhancement followed by a secondary suppression. The distinct regulations are achieved by transforming growth factor β-mediated selective inhibition of FoxP3− T-cell proliferation. This represents a novel mechanism of platelet-regulated CD4+ effector cell responses.