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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / transplantation
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CX3C Chemokine Receptor 1 / genetics
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CX3C Chemokine Receptor 1 / immunology
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Disease Models, Animal
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Dysbiosis / genetics
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Dysbiosis / immunology*
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Dysbiosis / microbiology
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Dysbiosis / pathology
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Gastrointestinal Microbiome / immunology
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Gene Expression Regulation
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Graft vs Host Disease / genetics
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Graft vs Host Disease / immunology*
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Graft vs Host Disease / microbiology
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Graft vs Host Disease / pathology
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interferon-gamma / immunology*
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Interleukin-17 / deficiency
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Interleukin-17 / genetics
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Interleukin-17 / immunology
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Interleukin-22
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Interleukins / genetics
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Interleukins / immunology*
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Intestines / immunology
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Intestines / microbiology
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Intestines / pathology
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Lymphocyte Depletion
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Pancreatitis-Associated Proteins / genetics
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Pancreatitis-Associated Proteins / immunology
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Phagocytes / cytology
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Phagocytes / immunology*
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology
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Signal Transduction
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T-Lymphocytes, Helper-Inducer
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T-Lymphocytes, Regulatory
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Whole-Body Irradiation
Substances
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CX3C Chemokine Receptor 1
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Cx3cr1 protein, mouse
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IFNG protein, mouse
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Il17a protein, mouse
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Interleukin-17
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Interleukins
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Pancreatitis-Associated Proteins
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Reg3g protein, mouse
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Interferon-gamma