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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Sep 14, 2023 |
| Title |
Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [ATAC-Seq] |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| 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.
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| Overall design |
MOUSE: Following 4 days of in vivo administration of 0.4 ug IL-25, C57BL/6 mice were sacrificed and lineage (CD8α [clone 53-6.7], CD4 [RM 4.4], CD3ε [145-2C11], γδTCR [UC7-13DS], TER119 [TER-119], B220 [RA3-6B2], CD11b [M1/70], NK1.1 [PK136], CD11c [N418], CD19 [MB19-1], Ly6G [1A8], and CD49b [DX5]) negative, ST2+ cells from the peritoneum and mesenteric lymph nodes were isolated and expanded in culture for 6 days in the presence of recombinant IL-7 and IL-33 (ILC2). HUMAN: Human ILC2s were isolated from a TrimaAccel LRS Chamber containing peripheral blood of health donors with the RosetteSep Human ILC2 Enrichment Kit (Stem Cell). ILC2s and pro-inflammatory conditioned ILC2s (pcILC2s) were cultured at 2.25 x 105 cells/mL in aMEM medium supplemented with 20% FBS and 1% Pen-Strep along with 50 ng/ml rIL-7, IL-2, IL-25, IL-4 and rIL-33 for the ILC2s and 50 ng/ml rIL-7, 50 ng/ml rIL-12, IL-2, rIL-1b, and 25 ng/ml rIL-18.
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| 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 |
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| Submission date |
May 08, 2023 |
| Last update date |
Jul 19, 2024 |
| Contact name |
SONIA LAURIE |
| E-mail(s) |
sonia.laurie@gmail.com
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| Organization name |
UNC CHAPEL HILL
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| Street address |
125 Mason Farm Road
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| City |
CHAPEL HILL |
| State/province |
NC |
| ZIP/Postal code |
27514 |
| Country |
USA |
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| Platforms (2) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (9)
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| GSM7307974 |
pcILC2, ATAC, rep1 |
| GSM7307975 |
pcILC2, ATAC, rep2 |
| GSM7307977 |
hILC2, ATAC, rep1 |
| GSM7307978 |
hILC2, ATAC, rep2 |
| GSM7307979 |
pc-hILC2, ATAC, rep1 |
| GSM7307980 |
pc-hILC2, ATAC, rep2 |
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| This SubSeries is part of SuperSeries: |
| GSE232003 |
Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation |
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| Relations |
| BioProject |
PRJNA970392 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE231999_RAW.tar |
3.5 Gb |
(http)(custom) |
TAR (of BW, NARROWPEAK) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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