Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE232003 | GEO | 2023/09/14
REPOSITORIES: GEO
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Project description: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.
2023-09-14 | GSE232002 | GEO
Project description: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.
2023-09-14 | GSE232001 | GEO
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.
2023-09-14 | GSE232000 | GEO
Project description: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.
2023-09-14 | GSE231999 | GEO
Project description:Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation
| PRJNA970384 | ENA
Project description:Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [ATAC-Seq]
| PRJNA970392 | ENA
Project description:Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [10X Multiome]
| PRJNA970390 | ENA
Project description:Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [scATAC-Seq]
| PRJNA970389 | ENA
Project description:Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [ChIP-Seq]
| PRJNA970391 | ENA
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.
2018-11-14 | GSE75344 | GEO