T Cell Recruitment to the Intestinal Stem Cell Compartment Drives Immune-Mediated Intestinal Damage after Allogeneic Transplantation

Fu, Ya–Yuan; Egorova, Anastasiya; Sobieski, Catherine; Kuttiyara, Jason; Calafiore, Marco; Takashima, Shuichiro; Clevers, Hans; Hanash, Alan M.

doi:10.1016/j.immuni.2019.06.003

Cited by 79 publications

(75 citation statements)

References 71 publications

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“…CD4 + T cells have been previously reported to localize to intestinal crypts and induce aGVHD by destroying cells within this niche ( 23 – 25 ). Consistent with this finding, we observed decreased colon length and increased goblet cell and crypt loss in aGVHD mice as compared with syngeneic controls ( Figure 9, A–D ; P < 0.004).…”

Section: Resultsmentioning

confidence: 99%

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

et al. 2020

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Intestinal GrA + Th cells in aGVHD represent a distinct Th lineage. Although the cellular sources were not defined, enhanced Gzma expression was previously observed in the intestines during aGVHD but only minimally in the skin and lymphoid organs (11). At 10 days post-HCT, we observed significantly increased expression of Gzma in both the small intestine (SI) and large intestine (LI) of mice that received allogeneic bone marrow and T cells as compared with syngeneic controls (P = 0.01 and P < 0.0001, respectively, Figure 1A). We observed a population of GrA + CD8 + T cells in all organs examined in allogeneic recipients that was present in lower percentages in syngeneic recipients (Figure 1, B and C). Unexpectedly, CD4 + T cells also produced GrA in allogeneic recipients and were the dominant population of GrA-producing T cells within the small and large intestines, the latter being where CD4 + T cells accounted for approximately 75% of the GrA-producing cells (Figure 1, B-D). A limited proportion of intestinal GrA + Th cells coexpressed GrB in the SI or LI, indicating that these cells did not acquire a classic cytotoxic phenotype (Figure 1E) (12-15). GrA + cells did not coexpress FOXP3 or IL-17A (Figure 1E) but exhibited partial coexpression of IFN-γ, which was slightly more pronounced in the LI versus the SI (~40% vs. ~30%, Figure 1E). To determine if GrA + Th cells were related to IFN-γ-producing Th1 cells, we analyzed lineage-specific cytokine and transcription factor expression (Supplemental Table 2; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.124465DS1) within intestinal CD3 + CD4 + T cells using time-of-flight cytometry (CyTOF). GrA + Th cells were spatially clustered, indicating that GrA expression is limited to a distinct population of Th cells and is not shared by multiple Th subsets (Figure 1F). In contrast, IFN-γ + Th cells were distributed between 2 major populations, those that spatially segregated with TNF + IL-2 + cells (i.e., prototypic Th1 cells) and those that partially overlapped with GrA + Th cells (Figure 1F). Cells that expressed high levels of GrA exhibited minimal overlap with other lineage-specific cytokines, many of which were expressed in low amounts (Supplemental Figure 1). These data indicate that GrA + Th cells are not typical Th1 cells and may represent a novel Th cell type that responds to signals involved with intestinal damage or inflammation. GrA is expressed by human Th cells in a PBMC-induced model of GVHD. Our data indicate that CD4 + Th cells are an important source of GrA and thus may be relevant to human GVHD. To examine this further, we adopted an established model (16) of human PBMC-induced GVHD in immune-compromised NRG mice. Briefly, human PBMCs from 2 individual donors were injected into NRG mice, and mice were monitored until they reached 20% body weight loss or a significant clinical score (>3). At this endpoint, mice were euthanized, and immune cells were isolated from the spleen, liver, SI, and LI and analyzed fo...

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Section: Resultsmentioning

confidence: 99%

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

et al. 2020

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“…Recent studies demonstrated that both CD4 + and CD8 + T cells had the potential to mediate injury to the ISC compartment in graft-versus-host disease model. The disease-causing T cells, after bone marrow transplantation (BMT)-mediated GI damage, targets the ISC niche as the primary site in the intestine under three-dimensional imaging examination ( 67 ). In addition, the recruitment of disease-causing T cells to the crypt base region resulted in the loss of ISC that expresses both the major histocompatibility complex class (MHC) I and II ( 67 ).…”

Section: Intestinal Stem Cell Nichementioning

confidence: 99%

“…The disease-causing T cells, after bone marrow transplantation (BMT)-mediated GI damage, targets the ISC niche as the primary site in the intestine under three-dimensional imaging examination ( 67 ). In addition, the recruitment of disease-causing T cells to the crypt base region resulted in the loss of ISC that expresses both the major histocompatibility complex class (MHC) I and II ( 67 ). In a similar report, another study explored the changes in the ISC niche using T cell-mediated injury in graft-versus-host disease (GVHD) model in vivo and intestinal organoid-T cell co-culture in vitro ( 55 ).…”

Section: Intestinal Stem Cell Nichementioning

confidence: 99%

Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases

et al. 2021

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The mammalian intestine is the largest immune organ that contains the intestinal stem cells (ISC), differentiated epithelial cells (enterocytes, Paneth cells, goblet cells, tuft cells, etc.), and gut resident-immune cells (T cells, B cells, dendritic cells, innate lymphoid cell, etc.). Inflammatory bowel disease (IBD), a chronic inflammatory disease characterized by mucosa damage and inflammation, threatens the integrity of the intestine. The continuous renewal and repair of intestinal mucosal epithelium after injury depend on ISCs. Inflamed mucosa healing could be a new target for the improvement of clinical symptoms, disease recurrence, and resection-free survival in IBD treated patients. The knowledge about the connections between ISC and immune cells is expanding with the development of in vitro intestinal organoid culture and single-cell RNA sequencing technology. Recent findings implicate that immune cells such as T cells, ILCs, dendritic cells, and macrophages and cytokines secreted by these cells are critical in the regeneration of ISCs and intestinal epithelium. Transplantation of ISC to the inflamed mucosa may be a new therapeutic approach to reconstruct the epithelial barrier in IBD. Considering the links between ISC and immune cells, we predict that the integration of biological agents and ISC transplantation will revolutionize the future therapy of IBD patients.

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“…Regarding the above phenomenon, the new niche for the implanted iLCs may play a vital role . In the early stage of transplantation, the cells may need to adapt to the new environment, and therefore, they maintain a slightly low activity. The activity of these implanted iLCs began to increase gradually approximately one week later.…”

Section: Discussionmentioning

confidence: 99%

Leydig‐like cells derived from reprogrammed human foreskin fibroblasts by CRISPR/dCas9 increase the level of serum testosterone in castrated male rats

Hua

Liu

Zhou

et al. 2020

J Cellular Molecular Medi

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| 3971 wileyonlinelibrary.com/journal/jcmm | INTRODUC TI ONMale hypogonadism due to testosterone deficiency is common in men aged 40-79 years, approximately 20% of whom are suffering from the disease, and incidence increases with age. 1,2 Several studies show that hypogonadism can lead to arteriosclerosis, decreased bone mineral density and depressed mood as well as fatigue and sexual dysfunction. [3][4][5] Testosterone replacement therapy (TRT) is AbstractIn the past few years, Leydig cell (LC) transplantation has been regarded as an effective strategy for providing physiological patterns of testosterone in vivo. Recently, we have successfully converted human foreskin fibroblasts (HFFs) into functional Leydig-like cells (iLCs) in vitro by using the CRISPR/dCas9 system, which shows promising potential for seed cells. However, it is not known whether the reprogrammed iLCs can survive or restore serum testosterone levels in vivo. Therefore, in this study, we evaluate whether reprogrammed iLCs can restore the serum testosterone levels of castrated rats when they are transplanted into the fibrous capsule. We first developed the castrated Sprague Dawley rat model through bilateral orchiectomy and subsequently injected extracellular matrix gel containing transplanted cells into the fibrous capsule of castrated rats. Finally, we evaluated dynamic serum levels of testosterone and luteinizing hormone (LH) in castrated rats, the survival of implanted iLCs, and the expression levels of Leydig steroidogenic enzymes by immunofluorescence staining and Western blotting. Our results demonstrated that implanted iLCs could partially restore the serum testosterone level of castrated rats, weakly mimic the role of adult Leydig cells in the hypothalamic-pituitary-gonadal axis for a short period, and survive and secrete testosterone, through 6 weeks after transplantation.Therefore, this study may be valuable for treating male hypogonadism in the future. K E Y W O R D SCRISPR/dCas9, human fibroblasts, Leydig-like cells, male hypogonadism, reprogramming, target gene activation

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T Cell Recruitment to the Intestinal Stem Cell Compartment Drives Immune-Mediated Intestinal Damage after Allogeneic Transplantation

Cited by 79 publications

References 71 publications

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases

Leydig‐like cells derived from reprogrammed human foreskin fibroblasts by CRISPR/dCas9 increase the level of serum testosterone in castrated male rats

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