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Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [ATAC-Seq]

ABSTRACT: Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. Previous work has shown that in mice and humans, ILC2s fail to reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating chromatin and transcriptomic analysis of marked, transplanted ILC2s at the single cell level, we identify a previously unreported population of converted ILC1-like cells in the small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines in vitro results in a mixed ILC1-ILC2 phenotype but was able to convert only an extremely small population of ILC2s to ILC1s as observed in vivo. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated-morbidity and mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Finally, circulating peripheral blood mononuclear cells from patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate, for the first time, that ILC2s fail to repopulate their protective niche after allo-HSCT in part due to conversion to a pro-pathogenic population marked by an ILC1-like chromatin state, providing novel insights into the contribution of ILC plasticity to aGvHD pathogenesis after allo-HSCT.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE231999 | GEO | 2023/09/14

REPOSITORIES: GEO

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Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [10X Multiome]

Project description:Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. Previous work has shown that in mice and humans, ILC2s fail to reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating chromatin and transcriptomic analysis of marked, transplanted ILC2s at the single cell level, we identify a previously unreported population of converted ILC1-like cells in the small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines in vitro results in a mixed ILC1-ILC2 phenotype but was able to convert only an extremely small population of ILC2s to ILC1s as observed in vivo. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated-morbidity and mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Finally, circulating peripheral blood mononuclear cells from patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate, for the first time, that ILC2s fail to repopulate their protective niche after allo-HSCT in part due to conversion to a pro-pathogenic population marked by an ILC1-like chromatin state, providing novel insights into the contribution of ILC plasticity to aGvHD pathogenesis after allo-HSCT.

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Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [ChIP-Seq]

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Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [scATAC-Seq]

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A clinical trial of Vedolizumab vs. placebo (dummy drug) for the prevention of intestinal Acute Graft Versus Host Disease (aGvHD), in patients undergoing allo-HSCT for a hematologic malignancy, (cancers that affect the blood and/or lymphatic system).

Project description:Main Objective: To evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in subjects who receive allo-HSCT as treatment for a hematologic malignancy or myeloproliferative disorder. Primary end point(s): The primary endpoint is intestinal aGvHD-free survival by Day +180 after allo HSCT. Intestinal aGvHD is defined as Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria.

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Project description:Lymphoid committed CD34+lin-CD10+CD24- progenitors undergo a rebound at month 3 after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the absence of acute graft-versus-host disease (aGVHD). Here, we analyzed transcriptional programs of cell-sorted circulating lymphoid committed progenitors and CD34+Lin-CD10- non lymphoid progenitors in 11 allo-HSCT patients having (n=5) or not developed (n=6) grade 2 or 3 aGVHD and in 7 age-matched healthy donors. Major deregulated pathways included protein synthesis, energy production, cell cycle regulation and cytoskeleton organization. Notably, genes from protein biogenesis, translation machinery and cell cycle (CDK6) were over-expressed in progenitors from patients in the absence of aGVHD compared with healthy donors and patients affected by aGVHD. Expression of many genes from the mitochondrial oxidative phosphorylation metabolic pathway leading to ATP production were more specifically increased in lymphoid committed progenitors in absence of aGVHD. This was also the case for genes involved in cell mobilization such as those regulating Rho GTPases activity. In all, we show that circulating lymphoid committed progenitors undergo profound changes in metabolism favoring cell proliferation, energy production and cell mobilization after allo-HSCT in humans. These mechanisms are abolished in case of aGVHD or its treatment, indicating a persistent cell-intrinsic defect after exit from bone marrow.

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Transcription factor Bcl11b controls identity and function of mature innate lymphoid cells type II

Project description:Type-2 innate lymphoid cells (ILC2s) promote anti-helminth responses and contribute to allergies. Though Bcl11b has been previously considered a T-lineage identity transcription factor (TF) that restrains the innate-cell genetic programs, we report here that Bcl11b is highly expressed in mature ILC2s and acts upstream of the key ILC2 TFs Gfi1, Gata-3, and of IL-33 receptor IL1rl1 (T1ST2). Additionally, Bcl11b-/- ILC2s de-repressed Rorγt, Ahr and IL-23 receptor, normally expressed in type-3 ILCs (ILC3s). Consequently, Bcl11b-/- ILC2s lost ILC2 functions and gained ILC3 functions, expanding in response to the protease allergen papain, however producing IL-17 and IL-22, and not IL-5 and IL-13, causing lung neutrophilia rather than eosinophilia, and diminished mucus production. Our results broaden Bcl11b's role from a T-cell only TF, and establishes that Bcl11b sustains mature ILC2 genetic and functional programs and lineage fidelity through positive regulation of essential ILC2 TFs and negative regulation of pivotal ILC3 TFs. RNA-seq analysis on sorted ILC2s from the mLNs of Bcl11bF/F Cre-ERT2 and wildtype mice at steady state following tamoxifen mediated deletion of Bcl11b

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Lipocalin-2 expression identifies an immuno-regulatory intestinal neutrophil population during GVHD

Project description:Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA-sequencing, we identified a Lipocalin-2 (LCN2)-expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD-severity, while the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced IGF-1R signaling in macrophages via the LCN2 receptor Slc22A17, which increased IL-10 production while reducing MHC-II expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity. LCN2-treatment did not reduce graft-versus-leukemia effects. In aGVHD patients LCN2 expression correlated with IL-10 expression in intestinal biopsies. We identified a novel intestinal LCN2+ neutrophil population that reduces aGVHD-severity by decreasing MHC-II expression while increasing IL-10 production in macrophages. Administration of LCN2 presents a novel approach against aGVHD to be tested in clinical trials.

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Project description:Acute Graft-versus-Host-Disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGVHD post HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited. Here, we report that hMSCs derived from three tissues divergently protected against aGVHD in a mouse model of this disease. Adipose tissue (AT)-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to bone marrow (BM)- and umbilical cord (UC)-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGVHD.

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Human ILC2 cells stimulated with IL-25, IL-33, or TSLP

Project description:ILC2 cells are a newly described cell type whose biology and contribution to disease are poorly understood. ILC2 cells are activated by allergens, viral infection, and/or epithelial damage via IL-33 and IL-25. ILC2 cells require IL-2, IL-7, IL-25 and IL-33 for their survival and expansion. In mice, ILC2s produce multiple mediators primarily associated with type 2 inflammation (IL-13, IL-5, IL-4, IL-6, IL-9, IL-10, GM-CSF, amphiregulin). ILC2 cells may contribute to the pathology of asthma through multiple mediators that include IL-13-independent pathways. Our goal is to compare transcriptional profiles of IL-33- or IL-25-activated ILC2 cells from blood to characterize these cells and to identify marker(s) that can be utilized to detect them in human tissue. ILC2 cells (Lineage negative, CRTH2+, CD161+, CD127+) were purified from human blood of 5 different donors by flow cytometry. The ILC2 yield ranged from 20,000 to 165,000 cells per donor (0.001-0.008% WBC). Purified ILC2s were expanded in vitro in the presence of IL-2, IL-7, IL-33 and IL-25 (each at 50 ng/ml) for 7-10 days. Expanded cells maintained the ILC2 phenotype (Lineage negative, CRTH2+, CD161+, CD127+). The cells were rested for 2 days in the presence of 1 ng/ml IL-2 and IL-7 and then treated in the presence of 1 ng/ml IL-2 and IL-7 with either media control, IL-25 (50 ng/ml), IL-33 (50 ng/ml), and/or TSLP (50 ng/ml) in combination, for 6 or 24 hours. Whole RNA was isolated via the RNeasy kit (Qiagen). Stratagene Universal Human Reference RNA was used as the reference.

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