IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33547295.
- Also identified by DOI 10.1038/s41467-021-21133-3 and PMC identifier 7865028.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>+</sup> Th/Tc1 cells and preferential expansion of IL-17<sup>-</sup>IL-22<sup>+</sup> Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8<sup>+</sup> T cells in the absence of CD4<sup>+</sup> T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8<sup>+</sup> T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1<sup>hi</sup> mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1<sup>hi</sup> 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.
Medical subject headings
- CD8-Positive T-Lymphocytes
- Dysbiosis
- Graft vs Host Disease
- Interferon-gamma
- Interleukins
- Phagocytes