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Background and aim Platelets are an able regulator of CD4 +  T cell immunity. Herein, the mechanisms underlying platelet-regulated effector responses of naïve CD4 +  T (Tn) cells were investigated. Methods Platelet–Tn cell co-cultures of human cells, genetically modified murine models, and high-throughput bioinformatic analyses were combined to elucidate molecular mechanisms of platelet-dependent regulation. Results Platelets exerted sophisticated regulation on effector responses of type 1, 2, and 17 T helper (Th1/Th2/Th17) and regulatory T (Treg) cells, in time-, concentration-, and organ-dependent manners and with close cooperation of transforming growth factor β (TGFβ) and platelet factor 4 (PF4). PF4 at low concentrations reinforced TGFβ signaling by heteromerizing with type III TGFβ receptor (TGFBRIII), and subsequently enhanced TGFBRII expression and TGFβ signaling. High-concentration PF4 had, however, opposite effects by directly binding to TGFBRII, blocking TGFβ–TGFBRII ligation, and thus inhibiting TGFβ signaling. Furthermore, platelet depletion markedly hampered Treg and Th17 responses in the spleen but not in the lymph nodes, blockade of platelet–Tn cell contact diminished platelet effects, while spleen injection of PF4-immobilized microparticles in PF4-deficient mice mimicked platelet effects, suggesting the importance of direct platelet–Tn contact and platelet-bound PF4 for the optimal regulatory effects by platelets. Conclusion Platelets exert context-dependent regulations on effector responses of Tn cells via PF4-TGFβ duet, suggesting new possibilities of platelet-targeted interventions of T cell immunity.

Platelets fine-tune effector responses of naïve CD4+ T cells via platelet factor 4-regulated transforming growth factor β signaling