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Apoptotic cell administration enhances pancreatic islet engraftment by induction of regulatory T cells and tolerogenic dendritic cells

Cellular & Molecular Immunology volume 10, pages 393–402 (2013)Cite this article

Abstract

Apoptotic cell transfer has been found to be able to facilitate engraftment of allograft. However, the underlying mechanisms remain to be fully understood. Here we demonstrate that intravenous administration of donor apoptotic splenocytes can promote pancreatic islet engraftment by inducing generation of tolerogenic dendritic cells (Tol-DCs) and expansion of CD4+Foxp3+ regulatory T cells (Tregs). In vivo clearance of either dendritic cells (DCs) or Tregs prevented the induction of immune tolerance by apoptotic cell administration. Transient elimination of Tregs using anti-CD25, monoclonal antibody (mAb) abrogated the generation of Tol-DCs after administration of apoptotic splenocytes. Reciprocally, depletion of DCs within CD11c-DTR mice using diphtheria toxin (DT) prevented the generation of Tregs in the recipients with administration of apoptotic splenocytes. Induction of Tregs by Tol-DCs required direct cell contact between the two cell types, and programmed death 1 ligand (PD-L1) played important role in the Tregs expansion. Apoptotic cell administration failed to induce Tol-DCs in IL-10-deficient and Smad3-deficient mice, suggesting that IL-10 and transforming growth factor-β (TGF-β) are needed to maintain DCs in the tolerogenic state. Therefore, we demonstrate that Tol-DCs promote the expansion of Tregs via PD-L1 on their surface and reciprocally Tregs facilitate Tol-DCs to maintain transplantation tolerance induced by apoptotic cells via secreting IL-10 and TGF-β.

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Acknowledgements

This work was supported by the National High Biotechnology Research and Development Program of China (2012AA020901 and 2006AA02A239), National Natural Science Foundation of China (81230074 and 30801000) and National Key Basic Research Program of China (2013CB530503).

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Author notes

  1. Cong Wu and Yi Zhang: The first two authors contributed to this work equally.

  2. Dr GY Chen, National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. E-mail: guoyouchen@immunol.org

  3. Dr XT Cao, National Key Laboratory of Medical Molecular Biology & Department of Immunology, Chinese Academy of Medical Sciences, Beijing 100005, China. E-mail: caoxt@immunol.org

Authors and Affiliations

  1. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

    Cong Wu & Xuetao Cao

  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China

    Cong Wu, Yi Zhang, Yingming Jiang, Quanxing Wang, Yao Long, Xuetao Cao & Guoyou Chen

  3. National Key Laboratory of Medical Molecular Biology & Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China

    Chunmei Wang

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Wu, C., Zhang, Y., Jiang, Y. et al. Apoptotic cell administration enhances pancreatic islet engraftment by induction of regulatory T cells and tolerogenic dendritic cells. Cell Mol Immunol 10, 393–402 (2013). https://doi.org/10.1038/cmi.2013.16

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