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Series GSE232002 Query DataSets for GSE232002
Status Public on Sep 14, 2023
Title Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [scATAC-Seq]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Although allogeneic hematopoietic stem cell transplantation (alloHSCT) is the preferred treatment for a variety of hematologic malignancies, its use is limited by the development of acute graft-versus-host disease (aGvHD). Type II innate lymphoid cells (ILC2s) are immune cells that play an important role in maintaining homeostasis in mucosal tissues. Previous work has shown that ILC2 cells fail to reconstitute after chemotherapy or stem cell transplantation, though the mechanism for this finding is unclear, making delineation of the mechanisms involved in their turnover and reconstitution could have a significant impact on transplant outcomes.

We evaluated the hypothesis that the loss of ILC2 cells post-transplant induced epigenetic changes that convert ILC2 cells to ILC1-like cells.  Strikingly, single-cell, multiomic analysis of donor-derived ILC2s after transplantation revealed a previously unreported population of ILC1-like cells that differentiate from ILC2s in the small intestine lamina propria (exILC2s). To recapitulate this transdifferentiation, we modeled skewing of ILC2s in vitro with IL-12, IL-1b, and IL-18 (termed proinflammatory cytokine conditioned ILC2s, pcILC2s) and observed a reduction in Type 2 lineage-defining regulatory factors and the acquisition of proinflammatory Type 1 characteristics consistent with the phenotype and function of the exILC2s recovered post-transplant. Excitingly, our approach confirms the skewed cell population expresses ILC1 associated Tbx21 and reveals Nr4a2, Foxo1, and Fli1 as additional putative drivers of the emergent ILC1-like exILC2s after alloHSCT.

To test whether ex vivo generated pcILC2s contribute to aGVHD-mediated mortality, we infused transdifferentiated donor WT or pcILC2s and measured the clinical score and survival of recipient mice after alloHSCT in a mismatched murine model. Unlike their unmanipulated WT ILC2 counterparts, our pcILC2s accelerated morbidity and mortality. Finally, peripheral blood cells from human patients with aGvHD have an altered chromatin landscape at ILC2-associated regions of accessibility compared to transplanted controls.

These data demonstrate that following transplantation ILC2s convert to a pro-pathogenic population ILC1-like cell state. These findings provide novel insights into the contribution of ILC plasticity to mucosal dysregulation and aGvHD pathogenesis after alloHSCT in a murine model and may inform new approaches for modulating innate lymphocytes in human disease.
Overall design Adults receiving allogeneic hematopoietic stem cell transplantations consented to have blood-derived PBMCs biobanked under Duke University IRB study protocol Pro00110250. We requested samples from 3-6 patients after alloHSCT with a diagnosis of acute graft-versus-host disease and 3-6 that were stable. Additionally, we requested a pre-HSCT sample and then one drawn as close as possible to the time of the aGVHD diagnosis, as well as 3 months and 1 year where available. Biobanked buffy coat samples were stored in liquid nitrogen prior to thawing and subsequent isolation of nuclei from viable cells.
Contributor(s) Laurie SJ, Foster II JP, Bruce DW, Bommiasamy H, Kolupaev OV, Yazdimamaghani M, Pattenden SG, Chao NJ, Sarantopoulos S, Parker JS, Davis IJ, Serody JS
Citation(s) 39019846
Submission date May 08, 2023
Last update date Jul 19, 2024
Contact name SONIA LAURIE
Organization name UNC CHAPEL HILL
Street address 125 Mason Farm Road
State/province NC
ZIP/Postal code 27514
Country USA
Platforms (2)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (15)
GSM7308366 Isolated ILC2, Healthy Donor, rep1
GSM7308367 Healthy Donor, rep1
GSM7308368 Healthy Donor, rep2
This SubSeries is part of SuperSeries:
GSE232003 Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation
BioProject PRJNA970389

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Supplementary file Size Download File type/resource
GSE232002_RAW.tar 7.2 Gb (http)(custom) TAR (of BED, CSV, H5, TBI, TSV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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