Platelet TGF-β triggers immunosuppression in ITP

Platelets are traditionally seen as the victims of an attack by the immune system in immune thrombocytopenia (ITP). In this issue of Blood, Wang et al use state-of-the-art methods to demonstrate that, on treatment with thrombopoietin receptor agonists (TPO-RAs), platelet-derived transforming growth factor β1 (TGF-β1) reprograms myeloid-derived suppressor cell (MDSC) function via the TGF-β/Smad pathway. This finding supports a novel role for platelets, putting them in charge of their own fate by restoring immune homeostasis.¹ 

ITP is an acquired hemorrhagic autoimmune disease characterized by increased platelet destruction and insufficient platelet production due to immune effector mechanisms. Much remains unknown of the complex pathophysiology of ITP; however, in recent years, robust progress has shown several mechanisms, including platelet autoantibodies, hyperactive T lymphocytes associated with impaired tolerance mechanisms characterized by dysfunctional T regulatory cells and MDSCs.² MDSCs are a heterogeneous group of immature myeloid cells with potent immunosuppressive functions. They have emerged as key contributors to self-tolerance breakdown as well as biomarkers of therapeutic efficacy in ITP.^3-5 Superimposed on the immune mechanisms involved in the pathophysiology of ITP is the novel finding that platelets themselves potentially play an active role in their own fate by their ability to regulate immunity.⁶ These immune properties are bestowed on platelets during their formation from megakaryocytes, allowing platelets to engage in a constant cross talk with diverse immune cells.⁷ Platelets are well equipped to elicit various nonhemostatic immune functions via many mechanisms.⁷ For example, 1 major immune molecule that platelets contain in their α granules is the immunosuppressive cytokine TGF-β1.^2,7-9 Decreased serum levels of TGF-β1 have been observed in patients with active ITP, and upregulated TGF-β1 has been closely associated with treatment responses.^8,10 

Whether platelets themselves can contribute to treatment-induced recovery from ITP via stimulating immune homeostasis has remained unclear. In the current study, Wang et al demonstrate a parallel increase in platelets and MDSCs in responders to TPO-RAs, which was associated with elevated levels of TGF-β1. Given that platelets are the largest pool of TGF-β1, the authors investigated the role of platelet-derived TGF-β1 in functionally reprogramming MDSCs using rigorous in vitro and in vivo methods. Using a mouse model of active ITP, based on anti-CD61 immune-sensitized splenocyte transfer into severe combined immunodeficient mice, it was found that TPO-RAs enhanced the inhibitory capability of MDSCs by arresting plasma cell differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Moreover, when PF4^cre+TGF-β1^fl/fl platelets were transfused into the active mouse model of ITP, no platelet count improvement or expansion of MDSCs was observed. In contrast, transfusion with PF4^cre-TGF-β1^fl/fl platelets resulted in higher platelet counts and MDSC percentages, indicating that TGF-β1 knockout platelets had limited or no rescuing capability compared with wild-type platelets. These results revealed the immune regulatory potential of platelet TGF-β1 on MDSC cell function. Furthermore, TGF-β1 blockade and targeted knockdown of Smad2/3 confirmed the participation of TGF-β/Smad signaling in platelet-modulated MDSCs.

There is growing evidence that TPO-RA therapy can induce a treatment-free remission in more than half of the responders. Along with clinical responses to TPO-RAs, improved regulatory T-cell activity, a restored regulatory B-cell compartment, and reduced phagocytic capacity of macrophages have been reported. The current article suggests that platelet recovery contributed to immune homeostasis at least partially through platelet-derived TGF-β1 (see figure). This may provide a theoretical explanation for the long-term responses seen in patients after tapering and discontinuation of TPO-RAs. It is increasingly clear that MDSCs are important players in maintaining immune tolerance and that they are impaired in numbers and function in active ITP. On the basis of the current findings, the authors suggest that early platelet responses to TPO-RA therapy might be partially due to platelet TGF-β–mediated immune regulation and that this may explain the long-term efficacy of the drug. More research is needed for improved understanding of tolerance breakdown causing ITP. Future studies should focus on expanding the profile of potential intracellular or surface markers to help monitor platelet-manipulated immune responses in ITP.

Conflict-of-interest disclosure: The authors declare no competing financial interests.