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

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-gamma (+) 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 Reg3 gamma -dependent manner. Transplantation of IFN-gamma -deficient donor CD8(+) T cells in the absence of CD4(+) T cells produces a phenocopy of SR-Gut-aGVHD. IFN-gamma deficiency in donor CD8(+) T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1(hi) mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1(hi) 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-gamma agonists in SR-Gut-aGVHD therapy. Pathogenesis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) remains unclear., Here the authors show in mouse models that dysbiosis caused by the expansion of Th/Tc22, as well as depletion of CX3CR1(hi) mononuclear phagocytes resulted from the reduction of Th/Tc1, contributes to SR-Gut-aGVHD onset.

Automated summary

The pathogenesis of SR-Gut-aGVHD involves the expansion of Th/Tc22 cells causing dysbiosis and reduction of Th/Tc1 cells leading to depletion of CX3CR1(hi) mononuclear phagocytes. Potential therapeutic strategies for SR-Gut-aGVHD include IL-22 antagonists and IFN-γ agonists.