A distinct “repair” role of regulatory T cells in fracture healing

Abstract

Regulatory T cells (Tregs) suppress immune responses and inflammation. Here, we described the distinct nonimmunological role of Tregs in fracture healing. The recruitment from the circulation pool, peripheral induction, and local expansion rapidly enriched Tregs in the injured bone. The Tregs in the injured bone displayed superiority in direct osteogenesis over Tregs from lymphoid organs. Punctual depletion of Tregs compromised the fracture healing process, which leads to increased bone nonunion. In addition, bone callus Tregs showed unique T-cell receptor repertoires. Amphiregulin was the most overexpressed protein in bone callus Tregs, and it can directly facilitate the proliferation and differentiation of osteogenic precursor cells by activation of phosphatidylinositol 3-kinase/protein kinase B signaling pathways. The results of loss- and gain-function studies further evidenced that amphiregulin can reverse the compromised healing caused by Treg dysfunction. Tregs also enriched in patient bone callus and amphiregulin can promote the osteogenesis of human pre-osteoblastic cells. Our findings indicate the distinct and nonredundant role of Tregs in fracture healing, which will provide a new therapeutic target and strategy in the clinical treatment of fractures.

Keywords

regulatory T cells / fracture healing / amphiregulin / non-union / osteogenesis

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82274026 and 81901884). We thank the patients and families for donating specimens for research. We acknowledge the central laboratory of Union Hospital for X-ray and microscopes imaging. We appreciate the Analytical and Testing Center of Tongji Medical School, Huazhong University of Science & Technology (HUST) for the micro-CT imaging.

Compliance with ethics guidelines

Conflicts of interest Tingting Wu, Lulu Wang, Chen Jian, Zhenhe Zhang, Ruiyin Zeng, Bobin Mi, Guohui Liu, Yu Zhang, and Chen Shi declare that they have no conflict of interest.

The study was approved by the Institutional Animal Care and Use Committee of Tongji Medical College, Huazhong University of Science and Technology (HUST) and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.

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