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
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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 7

Amelioration of SR-Gut-aGVHD by intestinal epithelial Ceacam1 deficiency is associated with enrichment of IL-22+ pTregs cells among intestinal intraepithelial lymphocytes.

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Amelioration of SR-Gut-aGVHD by intestinal epithelial Ceacam1 deficiency...
WT and IEC-Ceacam1–/– chimeras were engrafted with splenocytes together with TCD-BM from WT C57BL/6 donors as described for Figure 2. (A, B, and D–F) VillinCre-pos-Ceacam1fl/fl and VillinCre-neg-Ceacam1fl/fl recipients were engrafted with splenocytes together with TCD-BM from CD45.1 BALB/c donors and injected with 4-DEX. (A) Representative flow cytometry patterns and gating strategy of IL-22+Foxp3+IL-10+NRP-1–Helios–CD4+ T cells. (B) Mean ± SEM percentages and yields of %IL22+IL-17A–, IL-22+FoxP3+IL-10+, and IL-22+FoxP3+IL-10+NRP-1–Helios– cells in the colonic epithelium. n = 7 (WT), 6 (IEC-Ceacam1–/–). (C) Representative flow cytometry patterns and mean ± SEM percentages and yields of FoxP3+IL-22+IL-17A–CD4+ T cells in colon intraepithelial tissue. n = 7–9. (D) Representative flow cytometry patterns; mean ± SEM percentages and yields of FoxP3+IL-22– and FoxP3–IL-22+ cells in the colonic lamina propria. n = 4. (E and F) Representative flow cytometry patterns;mean ± SEM percentages and yields of T-bet+IFN-γ+ cells among CD4+ and CD8+ T cells in the colonic lamina propria. n = 4. Combined from 2 replicate experiments. P values are shown in B–D and F. Unpaired 2-tailed Student’s t test was used to compare 2 means.