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

Cell Mol Life Sci. 2022 Apr 18;79(5):247. doi: 10.1007/s00018-022-04279-1.


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.

Keywords: Effector cell responses; Naïve CD4+ T cells; Platelet factor 4; Platelets; Platelet–T cell interactions; Transforming growth factor β; Type II TGFβ receptor; Type III TGFβ receptor.

MeSH terms

  • Animals
  • Blood Platelets / metabolism
  • CD4-Positive T-Lymphocytes
  • Mice
  • Platelet Factor 4* / metabolism
  • T-Lymphocytes, Regulatory
  • Transforming Growth Factor beta* / metabolism


  • Transforming Growth Factor beta
  • Platelet Factor 4