Intestinal epithelial Ceacam1 deficiency prevents steroid-refractory acute gut graft-versus-host disease
Qingxiao Song, … , Paul J. Martin, Defu Zeng
Qingxiao Song, … , Paul J. Martin, Defu Zeng
Published September 9, 2025
Citation Information: JCI Insight. 2025;10(17):e186984. https://doi.org/10.1172/jci.insight.186984.
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Research Article Hematology Immunology Transplantation

Intestinal 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 nonrelapse death after allogeneic hematopoietic cell transplantation. High numbers of donor-type IL-22+ T cells, IL-22–dependent dysbiosis, and loss of antiinflammatory CX3CR1hi mononuclear phagocytes (MNPs) play critical roles in SR-Gut-aGVHD pathogenesis. CEACAM1 on intestinal epithelial cells (IECs) is proposed to regulate bacterial translocation and subsequent immune responses in the intestine. Here, with imaging mass cytometry (IMC), combined scRNA-Seq with ATAC-Seq, and high-dimensional flow cytometry analysis, we show that CEACAM1 expression was enhanced on IECs in murine and human SR-Gut-aGVHD. Ceacam1 deficiency on host IECs effectively prevented SR-Gut-aGVHD in murine models. Ceacam1 deficiency on IECs resulted in (i) higher numbers of IL-22+IL-10+Foxp3+CD4+ peripheral Tregs (pTregs) and lower numbers of conventional IL-22+CD4+ T (Tcon), Th/Tc1, and Th17 cells in the intestine; (ii) higher prevalence of beneficial commensal bacteria that augment colonic pTreg expansion, with lower prevalence of pathogenic bacteria; and (iii) higher numbers of antiinflammatory CD103–CX3CR1hi MNPs that produce indoleamine 2,3-dioxygenase (IDO) and IL-10, with lower numbers of proinflammatory CD103+CX3CR1lo MNPs that produce IL-6. Thus, specifically targeting IEC CEACAM1 represents a promising approach for prevention of SR-Gut-aGVHD.

Authors

Qingxiao Song, Moqian Zheng, Qinjian Li, Xiwei Wu, Boxi Lin, Tae Hyuk Kang, Hanjun Qin, Maciej Kujawski, Raju K. Pillai, James L. Lin, Ryotaro Nakamura, John Shively, Paul J. Martin, Defu Zeng

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Figure 5

Amelioration of SR-Gut-aGVHD by Ceacam1 deficiency in the host is associated with a reduction in IL-22+CD4+ Tcon cells but expansion of IL-22+IL-10+CD4+ pTregs in the MLN.

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Amelioration of SR-Gut-aGVHD by Ceacam1 deficiency in the host is associ...
WT and IEC-Ceacam1–/– chimeras were engrafted with splenocytes together with TCD-BM from WT C57BL/6 donors and induced to develop SR-Gut-GVHD, as described for Figure 2. On day 25, T cell subset in MLNs from WT or IEC-Ceacam1–/– recipients were analyzed. (A) UMAP plot generated from IL-22+IL17A–CD4+ (Th22) cells in MLNs of both WT and IEC-Ceacam1–/– chimeras. (B) Mean ± SEM percentages of individual populations. (C) Mean ± SEM percentages of populations 4 and 5 (Pop4 and Pop5). (D) Heatmap plot of IFN-γ, CD127, T-bet, GM-CSF, AHR, IL-2, CCR6, FoxP3, PD-1, IL-17A, RORγt, CEACAM1, and IL-10 expression. (E) Representative flow cytometry pattern and gating strategy of FoxP3, AHR, RORγt and IL-10 in Th22 cells. (F) Mean ± SEM percentage of FoxP3–AHR+, FoxP3–RORγt+, and FoxP3+RORγt– subsets in Th22 cells and of IL10+ in Foxp3+RORγt– Th22 cells; and yields of the respective subsets. (G) Representative flow cytometry pattern and gating strategy for PD-1, CCR6, and T-bet in FoxP3+RORγt– and Foxp3–RORγt+ Th22 subsets. (H) Representative flow cytometry patterns and mean ± SEM percentage of T-bet+IFN-γ+ subset in CD4+ T cells and yields in WT and IEC-Ceacam1–/– chimeras. n = 10 (WT), n = 8 (IEC-Ceacam1–/–), from 2 replicate experiments. P values are shown in C and E–H. C and F–H: Unpaired 2-tailed Student’s t test.