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IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice

Author

Listed:
  • Qingxiao Song

    (The Beckman Research Institute of City of Hope
    The Beckman Research Institute of City of Hope
    Fujian Institute of Hematology, and Fujian Medical University Union Hospital)

  • Xiaoning Wang

    (The Beckman Research Institute of City of Hope
    The Beckman Research Institute of City of Hope
    The First Affiliated Hospital of Xi’an Jiaotong University)

  • Xiwei Wu

    (The Beckman Research Institute of City of Hope)

  • Tae Hyuk Kang

    (The Beckman Research Institute of City of Hope)

  • Hanjun Qin

    (The Beckman Research Institute of City of Hope)

  • Dongchang Zhao

    (The Icahn School of Medicine at Mount Sinai Hospital)

  • Robert R. Jenq

    (University of Texas MD Anderson Cancer Center)

  • Marcel R. M. Brink

    (Memorial Sloan Kettering Cancer Center)

  • Arthur D. Riggs

    (The Beckman Research Institute of City of Hope)

  • Paul J. Martin

    (University of Washington)

  • Yuan-Zhong Chen

    (Fujian Institute of Hematology, and Fujian Medical University Union Hospital)

  • Defu Zeng

    (The Beckman Research Institute of City of Hope
    The Beckman Research Institute of City of Hope)

Abstract

Efforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17−IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.

Suggested Citation

  • Qingxiao Song & Xiaoning Wang & Xiwei Wu & Tae Hyuk Kang & Hanjun Qin & Dongchang Zhao & Robert R. Jenq & Marcel R. M. Brink & Arthur D. Riggs & Paul J. Martin & Yuan-Zhong Chen & Defu Zeng, 2021. "IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21133-3
    DOI: 10.1038/s41467-021-21133-3
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