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Adoptive transfer of IFN-γ-induced M-MDSCs promotes immune tolerance to allografts through iNOS pathway

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Abstract

Aim and objective

Efficient production of monocytic myeloid-derived suppressor cells (M-MDSCs) with stable immunosuppressive function is crucial for immunomodulatory cell therapy for many diseases such as transplant rejection, graft-versus-host disease and autoimmune diseases.

Methods

We used M-CSF as growth factor for myeloid progenitor cell differentiation and activated them with IFN-γ during early stage in vitro to produce M-MDSCs. The cell phenotypes were determined using flow cytometry, the immunosuppressive function and mechanisms were determined by skin grafted mouse models and genetic modified mice.

Results

IFN-γ treatment endows these cell strong immunosuppressive function by inhibition of T cell proliferation and cytokine productions. The phenotype of these cells also changed towards M-MDSCs. IFN-γ significantly upregulated iNOS expression in these M-MDSCs and inhibition of this molecule significantly reversed their immune regulatory function. The functional stability of induced M-MDSCs by IFN-γ was tested in vivo by transferring them to alloskin-grafted mice. Adoptive transfer of these cells significantly prolonged allograft survival and promoted immune tolerance, whereas iNOS deficiency in these cells reversed this effect.

Conclusions

We established one M-MDSCs-inducting protocol with the combination of M-CSF and IFN-γ in vitro. M-CSF+IFN-γ-induced M-MDSCs are promising to prevent graft rejection by immune regulation.

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Acknowledgements

The authors appreciated Drs. Yuzhu Hou and Peng Wang for their critical reviewing our manuscript, and Mrs. Ling Li for her excellent laboratory management. This work was supported by Grants from the National Natural Science Foundation for General and Key Programs (81530049, U1738111, Y.Z.), the National Key Research and Development Program of China (2017YFA0105002, 2017YFA0104402, Y.Z.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030301, XDA16030300, Y.Z.), and The China Manned Space Flight Technology Project (TZ-1).

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Author notes

  1. Fan Yang, Yang Li and Weilong Zou equally contributed as the first authors.

Authors and Affiliations

  1. Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China

    Fan Yang, Yang Li, Yanan Xu & Yong Zhao

  2. Surgery of Transplant and Hepatopancrobiliary, The General Hospital of Chinese People’s Armed Police Forces, Beijing, China

    Weilong Zou

  3. Department of Radiation Oncology, Peking University Third Hospital, Beijing, China

    Hao Wang

  4. Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Beijing, 100020, China

    Wei Wang

  5. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China

    Yong Zhao

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  1. Fan Yang
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  2. Yang Li
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  4. Yanan Xu
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  5. Hao Wang
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Correspondence to Wei Wang or Yong Zhao.

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Yang, F., Li, Y., Zou, W. et al. Adoptive transfer of IFN-γ-induced M-MDSCs promotes immune tolerance to allografts through iNOS pathway. Inflamm. Res. 68, 545–555 (2019). https://doi.org/10.1007/s00011-019-01237-9

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  • DOI: https://doi.org/10.1007/s00011-019-01237-9

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