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

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-?⁺ 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?-dependent manner. Transplantation of IFN-?-deficient donor CD8⁺ T cells in the absence of CD4⁺ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-? 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-? agonists in SR-Gut-aGVHD therapy.

SUBMITTER: Song Q 

PROVIDER: S-EPMC7865028 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature