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

UID: 10773

Author(s): Song, Qingxiao, Zeng, Defu

Description
Summary from the GEO: "CD4+ and CD8+ T cells can reciprocally differentiate into Th/Tc1, Th/Tc17 and Th/Tc22. Although alloreactive Th/Tc1 cells play a critical role in initiating pathogenesis of gut acute graft-versus-host disease (Gut-aGVHD), the pathogenic T cells in steroid-resistant Gut-aGVHD (SR-Gut-aGVHD) remains unclear. Here, we show that in murine models of SR-Gut-aGVHD, the pathogenesis is associated with reduction of IFN-g+ Th/Tc1 and IL-17A+IL-22- Th/Tc17 but expansion of IL-17-IL-22+ Th/Tc22, particularly Tc22 cells. IL-22 from Th/Tc22 cells causes dysbiosis. Using a Gut-aGVHD model induced by alloreactive IFN-g-/- CD8+ T cells, we show that the Gut-aGVHD pathogenesis requires both dysbiosis and depletion of CX3CR1hi mononuclear phagocytes (MNP) that regulate intestinal bacterial translocation. Absence of IFN-g leads to preferential expansion of Tc22 that induce dysbiosis by augmenting RegIIIg production, and depletion of CX3CR1hi MNP via its PD-1 interaction with tissue PD-L1. Interestingly, SR-Gut-aGVHD is also associated with depletion of CX3CR1hi MNP that reduces expansion of Tc22 under steroid treatment. Our studies indicate that expansion of Th/Tc22, dysbiosis, and depletion of CX3CR1hi MNP cells play critical roles in SR-Gut-aGVHD pathogenesis. These results provide new avenue towards studies in patients and call for caution in clinical testing of IL-22 agonists or IFN-g antagonist in patients."

Overall design from the GEO: "Experiments of the relationship between the SR-Gut-aGVHD pathogenesis and the regulation of IFN-γ+ Th/Tc1, IL-17A+IL-22- Th/Tc17 and IL-17-IL22+Th/Tc22 cells."
Subject of Study
Mus musculus
Subject(s)
Bacterial Translocation
CD8-Positive T-Lymphocytes
Chemokines, CX3C
Dysbiosis
Graft vs Host Disease
Interleukin-17
Interleukins
Phagocytes
Programmed Cell Death 1 Receptor
T-Lymphocytes, Cytotoxic
Access via GEO

Compressed CSV file containing XML associated with the experiment
Accession #: GSE159031

Access via SRA

Sequencing of 27 stool samples
Accession #: SRP286400

Access via BioProject

Additional information about the overall inititative.
Accession #: PRJNA667450

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
Associated Publications
Song Q, Wang X, Wu X, et al. IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice. Nature Communications. 2021; 12:805.
Data Type
Genomic
Equipment Used
PACBIO Sequel System

Sequel Systems support the full range of SMRT Sequencing applications for generating genomes, transcriptomes, and epigenomes.

Software Used
SRA Toolkit

The NCBI SRA Toolkit enables reading ("dumping") of sequencing files from the SRA database and writing ("loading") files into the .sra format.

Dataset Format(s)
CSV, XML, SRA
Data Tool(s)
RNA Seq
Dataset Size
201.9 Kb (CSV), 0.20 Gb (SRA)
Data Catalog Record Updated
2023-12-07