Platelet-derived TGF-β1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia

• Published in: Blood Vol. 144; no. 1; pp. 99 - 112
• Main Authors: Wang, Lingjun, Wang, Haoyi, Zhu, Mingfang, Ni, Xiaofei, Sun, Lu, Wang, Wanru, Xie, Jie, Li, Yubin, Xu, Yitong, Wang, Ruting, Han, Shouqing, Zhang, Ping, Peng, Jun, Hou, Ming, Hou, Yu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.07.2024
• Subjects: Adult; Animals; Blood Platelets - immunology; Blood Platelets - metabolism; Cellular Reprogramming; Female; Humans; Male; Mice; Mice, SCID; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Purpura, Thrombocytopenic, Idiopathic - immunology; Purpura, Thrombocytopenic, Idiopathic - metabolism; Purpura, Thrombocytopenic, Idiopathic - pathology; Signal Transduction; Transforming Growth Factor beta1 - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023022738

•Platelet-derived TGF-β1 modulates MDSC function and profiling via TGF-β/Smad pathway in ITP.•Beyond an indicator of treatment response, platelet TGF-β paves the way for immune homeostasis in immune-mediated thrombocytopenia. [Display omitted] Platelet α-granules are rich in transforming growth factor β1 (TGF-β1), which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-β/Smad pathways in TPO-RA–corrected MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-β1–deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that patients with ITP achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-β1 induces the expansion and functional reprogramming of MDSCs via the TGF-β/Smad pathway. These data indicate that platelet recovery not only serves as an end point of treatment response but also paves the way for immune homeostasis in immune-mediated thrombocytopenia. Immune thrombocytopenia is caused by the destruction of platelets arising from immune attack, and it has been considered that successful therapy results in an alteration of the immune milieu from which platelets passively benefit. Wang and colleagues suggest that platelets may play a more active role in this immune modulation through the secretion of transforming growth factor β1 (TGF-β1), leading to increased myeloid-derived suppressor cells and modulation of T-cell subsets.