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 2

Host Ceacam1 deficiency ameliorates SR-Gut-aGVHD but not untreated GVHD.

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Host Ceacam1 deficiency ameliorates SR-Gut-aGVHD but not untreated GVHD....
(A and B) BALB/c recipients received T cell–depleted BM (TCD-BM) with or without splenocytes from WT C57BL/6 donors. Recipients of TCD-BM and splenocytes received 1 or 4 DEX injections after HCT. Colon epithelial CEACAM1 expression was analyzed on day 25 by IHC and flow cytometry. (A) Representative images. One representative micrographic photo (original magnification, ×100) is shown of 4 replicate mice in each group. (B) MFI of CEACAM1. n = 5–6 combined from 2 replicate experiments. (C) WT (WT Rec) or Ceacam1–/– BALB/c (Ceacam1–/– Rec) recipients received WT C57BL/6 splenocytes and TCD-BM (untreated GVHD). Original body weight, mice without diarrhea, and survival are shown as percentages. n = 15 from 2 replicate experiments. (D) Experimental conditions as in C, except that recipients received 4-DEX injection (SR-Gut-aGVHD). n = 10 from 2 replicate experiments. (E) Colon histopathology was evaluated on day 25. Representative micrographic photos (original magnification, ×200) and percentage of mice with indicated histopathological scores. n = 4/group from 2 replicate experiments. (F) Mean ± SEM of yield of CD11b+Ly6G+ cells. (G) Means ± SEM of yield of H2Kb+TCRβ+CD4+ T cell. n = 4 mice/group from 2 experiments. (H) Means ± SEM of %CEACAM1+H2Kb– cells. (I) IHC staining of CEACAM1 (purple), CD11b (yellow) and CD3 (teal) in colon on day 25. Representative photomicrographs (original magnification, x100) are shown. The P value is shown in B, F, G, and I. Nonlinear regression (curve fit) was used for body weight comparisons. Log-rank test was used for survival comparisons. B and F–I: unpaired 2-tailed Student’s t test).