Intestinal epithelial Ceacam1 deficiency prevents steroid-refractory acute gut graft-versus-host disease
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
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
View: Text | PDF
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

×

Figure 4

Amelioration of SR-Gut-aGVHD by Ceacam1 deficiency in IECs is associated with distinct CD4+ Tcon cells and pTreg subsets and gene signaling pathways in MLN cells.

Options: View larger image (or click on image) Download as PowerPoint
Amelioration of SR-Gut-aGVHD by Ceacam1 deficiency in IECs is associated...
WT and IEC-Ceacam1–/– (CC1–/–) chimeras were engrafted with donor cells and treated with 4-DEX as described for Figure 3. On day 25, CD4+ T cells from MLNs of WT or IEC-CC1–/– recipients were sorted for scRNA plus ATAC sequencing. (A) Subclustering t-SNE of all CD4+ T cells. The 15 clusters are indicated. (B) t-SNE plot of cell cycle. (C) Comparison of percentage of individual cluster of cell cycle. (D) Dot plot of immunomodulatory genes across all clusters. (E) Heatmap showing the differential transcription factor motif accessibility. (F) t-SNE showing the lineage trajectory ordered from naive cells to Tregs (cluster 14) or effector T cells (other clusters). The diagram shows changes in CD4+ T clusters in Ceacam1–/– chimeras compared with WT chimeras. ↑, increase; ↓, decrease; C1, naive T cells; C3, cycling CD4+ T cells (Ceacam1–/– chimera only); C5, G1 resting Th17; C7, Th1-, Th2-, Th17-, and Th22-like; C8, Th2; C11, G2M/S proliferating Th17; C12, anergic Th1; C13, Th1; C14, pTregs. (G) Comparison of percentages of individual clusters. (H) Bubble plot showing enriched KEGG, REACTOME, and HALLMARK signature pathways by comparing IEC-CC1–/– and WT. (I) Dot plot of immunomodulatory genes of clusters 5, 12, and 14, comparing IEC-CC1–/– and WT. (J and K) GSEA plot of HALLMARK apoptotic pathway (J) and BP_GO oxidative phosphorylation pathway (K) of cluster 14 by comparing IEC-CC1–/– recipients with WT recipients. abs(NES), absolute value of normalized enrichment score.