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

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 () and Defu Zeng ()
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Qingxiao Song: The Beckman Research Institute of City of Hope
Xiaoning Wang: The Beckman Research Institute of City of Hope
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

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21133-3

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