Adoptive transfer of IFN-γ-induced M-MDSCs promotes immune tolerance to allografts through iNOS pathway
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.
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.
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.
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.
KeywordsMyeloid-derived suppressor cells Immune tolerance Nitric oxide Transplantation
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).
Compliance with ethical standards
Conflict of interest
The authors herein declare that all authors have no competing financial interests.
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