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 3

SR-Gut-aGVHD is ameliorated by Ceacam1 deficiency on host IECs but not on hematopoietic cells.

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SR-Gut-aGVHD is ameliorated by Ceacam1 deficiency on host IECs but not o...
(A–C) WT BALB/c recipients received TCD-BM from WT or Ceacam1–/– BALB/c donors to generate the chimeras. Two months after bone marrow reconstitution, WT or HC-Ceacam1–/– chimeras were lethally irradiated and engrafted with splenocytes and TCD-BM from WT C57BL/6 donors, and the recipients were given 4-DEX treatment. (A) Original body weight and mice without diarrhea are shown as percentages. n = 18 (WT chimeras), 15 (host HC-Ceacam1–/– chimeras) from 2 replicate experiments. (B) Histopathology of colon on day 25. Representative photomicrographs (original magnification, ×200) and percentage of mice with indicated histopathological scores. n = 6 (WT), n = 8 (HC-Ceacam1–/–), from 2 replicate experiments. (C) IHC staining of CEACAM1 (purple), CD11b (yellow) and CD3 (teal) on colon day 25 after HCT. Representative photomicrographs (original magnification, ×100). Mean ± SEM percentage of CEACAM1+ area relative to the whole slide. (D–H) WT and Ceacam1–/– BALB/c recipients received TCD-BM from WT BALB/c donors to generate chimeras. Then the irradiated WT or IEC-Ceacam1–/– chimeras received splenocytes and TCD-BM from WT C57BL/6 donors. (D) Original body weight and mice without diarrhea are shown as percentages. n = 18 (WT), 15 (IEC-Ceacam1–/–), from 2 replicate experiments. (E) Histopathology of colon on day 25. Representative photomicrographs (original magnification, ×200) and percentage of mice with indicated histopathological scores. n = 4 (WT), 5 (IEC-Ceacam1–/–), from 2 replicate experiments. (F) IHC staining of CEACAM1 (purple), CD11b (yellow), and CD3 (teal) on colon on day 25. Representative photomicrographs (original magnification, ×100). Mean ± SEM percentage of CEACAM1+ area relative to the whole slides. (G and H) Mean ± SEM percentage (G) and yield of CD4+ and CD8+ T cells (H) in colon intraepithelial tissue. P values are shown in E–H. D: nonlinear regression, curve fit; E–H; unpaired 2-tailed Student’s t test.