title: The calcineurin-NFAT axis controls allograft immunity in myeloid-derived suppressor cells through reprogramming T cell differentiation.
abstract: While cyclosporine (CsA) inhibits calcineurin and is highly effective in prolonging rejection for transplantation patients, the immunological mechanisms remain unknown. Herein, the role of calcineurin signaling was investigated in a mouse allogeneic skin transplantation model. The calcineurin inhibitor CsA significantly ameliorated allograft rejection. In CsA-treated allograft recipient mice, CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs) were functional suppressive immune modulators that resulted in fewer gamma interferon (IFN-γ)-producing CD8(+) T cells and CD4(+) T cells (T(H)1 T helper cells) and more interleukin 4 (IL-4)-producing CD4(+) T cells (T(H2)) and prolonged allogeneic skin graft survival. Importantly, the expression of NFATc1 is significantly diminished in the CsA-induced MDSCs. Blocking NFAT (nuclear factor of activated T cells) with VIVIT phenocopied the CsA effects in MDSCs and increased the suppressive activities and recruitment of CD11b(+) Gr1(+) MDSCs in allograft recipient mice. Mechanistically, CsA treatment enhanced the expression of indoleamine 2,3-dioxygenase (IDO) and the suppressive activities of MDSCs in allograft recipients. Inhibition of IDO nearly completely recovered the increased MDSC suppressive activities and the effects on T cell differentiation. The results of this study indicate that MDSCs are an essential component in controlling allograft survival following CsA or VIVIT treatment, validating the calcineurin-NFAT-IDO signaling axis as a potential therapeutic target in transplantation.
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University, Health Science Center, Beijing, China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Xue
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.
authors.forename: Jiongbo
authors.initials: J
authors.lastname: Liao
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.
authors.forename: Huanrong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China liugw@fudan.edu.cn.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
mesh_terms: D064591:Allografts / Q000187:drug effects / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D019703:Calcineurin / Q000276:immunology / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology; D006085:Graft Survival / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050778:NFATC Transcription Factors; D009842:Oligopeptides; C121611:VIVIT peptide; D007371:Interferon-gamma; D016572:Cyclosporine; D019703:Calcineurin