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Intestine epithelial Ceacam1 deficiency prevents steroid-refractory acute gut graft-versus-host disease

ABSTRACT: Steroid refractory gut acute graft-versus-host disease (SR-Gut-aGVHD) is the major cause of non-relapse death after allogeneic hematopoietic cell transplantation, due to poor understanding its pathogenesis. We recently reported that increase of donor-type IL-22+ T cells, IL-22-dependent dysbiosis, and loss of anti-inflammatory CX3CR1hi mononuclear phagocytes (MNP) play critical roles in SR-Gut-aGVHD pathogenesis, but the mechanisms remain unclear. Ceacam1 on intestinal epithelial cells (IECs) is proposed to regulate bacterial translocation and subsequent immune response in the gut tissues. Here, with imaging mass cytomtory (IMC), combined scRNA-Seq and ATAC-Seq, as well as high dimensional flow cytometry analysis, we show that Ceacam1 expression is enhanced on IECs in murine and human SR-Gut-aGVHD. Ceacam1 deficiency on host IECs effectively prevents SR-Gut-aGVHD in murine models. Ceacam1 deficiency on IECs results in 1) increase in frequencies of IL-22+IL-10+Foxp3+CD4+ peripheral Tregs (pTregs) while reducing conventional IL-22+CD4+ T (Tcon), Th/Tc1, and Th17 cells; 2) increase of beneficial commensal bacterial that augment colonic pTregs expansion, while reducing pathogenic bacteria and blocking E. Coli’s interaction with IECs; and 3) increase of anti-inflammatory CD103-CX3CR1hi MNP that produce IDO and IL-10, while reducing pro-inflammatory CD103+CX3CR1lo MNP that produce IL-6. Thus, specific targeting IEC Ceacam1 represents a novel approach for prevention of SR-Gut-aGVHD.

ORGANISM(S): Mus musculus

PROVIDER: GSE268993 | GEO | 2026/05/28

REPOSITORIES: GEO

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

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2020-12-27 | GSE159031 | GEO

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

2020-12-27 | GSE159418 | GEO

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2014-05-09 | E-GEOD-56444 | biostudies-arrayexpress

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2014-05-09 | GSE56444 | GEO

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2025-11-19 | GSE310343 | GEO

Facile Induction of Immune Tolerance by an Interleukin-2-TGF-β Surrogate Agonist

Project description:CD4⁺ regulatory T (Treg) cells are essential for establishing and maintaining immune tolerance. Peripherally induced Tregs (pTregs), which differentiate from mature conventional CD4⁺ T cells in the periphery, complement Tregs generated in the thymus during T cell development by broadening Treg reactivity in response to changing self and the environment. Although both TGF-β and Interleukin-2 (IL-2) synergistically promote functional pTreg development in vitro, their combined roles in inducing pTreg generation in vivo have not been thoroughly characterized and therefore are yet to be exploited for tolerizing immunotherapy. The principal limitation to in vivo use of IL-2 and TGF-β is their pleiotropy and inability to ensure co-delivery of SMAD and STAT signaling to the same cell. To overcome these challenges, we designed an IL-2-TGF-β surrogate agonist by creating a fusion protein between IL-2 and a low-affinity TGF-β mimic agonist derived from a Helminth parasite. This IL-2-TGF-β surrogate agonist was easily expressed and purified and enabled simultaneous cis-activation of both IL-2 and TGF-β signaling specifically in IL-2 receptor-expressing T cells. This IL-2-TGF-β surrogate agonist robustly induced antigen-specific, functional, and stable pTregs in vivo within peripheral lymphoid organs in OVA- or MOG35-55-immunized mice. The induced pTregs phenotypically resemble effector and colonic Rorγt⁺ pTregs, with the potential to efficiently migrate into the gut and suppress intestinal inflammation. Treatment with this agonist effectively quelled immune activation in mouse models of allergen-induced allergic inflammation and self-antigen-driven autoimmune neuroinflammation, portending a strategy for the targeted induction of antigen-specific pTregs in vivo to induce immune tolerance in inflammatory and autoimmune diseases.

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Project description:Systemic infection induces conserved physiological responses that include both resistance and ‘tolerance of infection’ mechanisms. Among these responses, temporary anorexia associated with an infection is often beneficial. It poses, however, a problem for the trillions of microbes residing in the gastrointestinal tract, as they also experience reduced substrate availability. We hypothesized that under anorectic conditions caused by infection, the host might activate protective mechanisms to support the gut microbiota during the acute phase of the disease. Here, we report that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α1,2-fucosylation of the small intestine epithelial cells (IEC). The process requires sensing of TLR agonists and production of IL-23 by dendritic cells, activation of innate lymphoid cells and expression of α1,2-Fucosyltransferase-2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is utilized by microbiota, as shown using reporter bacteria and by transcriptional profiling of the gut microbiome. Fucosylation also reduces the expression of bacterial virulence genes within the commensal gut microbiome and improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host’s resources to maintain host-microbial interactions during pathogen-induced stress. RNA-Seq analysis of the murine gut microbiome following LPS exposure. Fut2-/- (B6.129X1-Fut2tm1Sdo/J) mice were backcrossed greater than 7 generations to BALB/c. Fut2-/- (KO) and Fut2+/- (Het) animals were analyzed.

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