Runx3 drives a tissue residency program that is absent in CD4+ T cells [ATAC-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE198611 | GEO | 2022/05/24
REPOSITORIES: GEO
Similar Datasets
Project description:Pattens of tissue-residency differs between CD4+ and CD8+ memory T cells in evironmentally exposed organs. The lineage-controlling transcription factor Runx3, expressed in CD8+ T cells, is responsible for shaping a tissue-resident gene network in response to the cytokine TGF-b. While the lack of Runx3 by CD4+ T cells precludes these transcriptional changes, Runx3-overexpression in CD+ T cells enable phenotypical, transcriptional and functional changes to allow residency.
2022-05-24 | GSE182511 | GEO
Project description:Tissue-resident memory CD8+ T cells (Trm) are positioned at common sites of pathogen exposure where they elicit rapid and robust protective immune responses. However, the molecular signals controlling Trm differentiation and homeostasis are not fully understood. Here we show that mouse Trm precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory populations at the levels of gene expression and chromatin accessibility. Exploiting computational and functional RNAi in vivo screens, we identified the transcription factor (TF) Runx3 as a key regulator of Trm differentiation and homeostasis. Runx3 was required to establish Trm populations in diverse tissue environments and supported expression of critical tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Analysis of the accessibility of Runx3 target genes in Trm-precursor cells revealed a distinct regulatory role for Runx3 in controlling Trm differentiation despite relatively widespread and uniform expression among all CD8+ T cell subsets. Further, we show that human and murine tumor-infiltrating lymphocytes (TIL) share a core tissue-residency gene-expression signature with Trm. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ TIL failed to accumulate in tumors, resulting in greater rates of tumor growth and mortality. Conversely, overexpression of Runx3 enhanced TIL abundance, delayed tumor growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of Trm differentiation, these results provide novel insight into the signals that promote T cell residency in tissues, which could be leveraged to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.
2018-01-03 | GSE106107 | GEO
Project description:Tissue-resident memory CD8+ T cells (Trm) are positioned at common sites of pathogen exposure where they elicit rapid and robust protective immune responses1,2. However, the molecular signals controlling Trm differentiation and homeostasis are not fully understood. Here we show that mouse Trm precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory populations at the levels of gene expression and chromatin accessibility. Exploiting computational and functional RNAi in vivo screens, we identified the transcription factor (TF) Runx3 as a key regulator of Trm differentiation and homeostasis. Runx3 was required to establish Trm populations in diverse tissue environments and supported expression of critical tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Analysis of the accessibility of Runx3 target genes in Trm-precursor cells revealed a distinct regulatory role for Runx3 in controlling Trm differentiation despite relatively widespread and uniform expression among all CD8+ T cell subsets. Further, we show that human and murine tumor-infiltrating lymphocytes (TIL) share a core tissue-residency gene-expression signature with Trm. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ TIL failed to accumulate in tumors, resulting in greater rates of tumor growth and mortality. Conversely, overexpression of Runx3 enhanced TIL abundance, delayed tumor growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of Trm differentiation, these results provide novel insight into the signals that promote T cell residency in tissues, which could be leveraged to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.
2017-12-15 | GSE107289 | GEO
Project description:Tissue-resident memory CD8+ T cells (Trm) are positioned at common sites of pathogen exposure where they elicit rapid and robust protective immune responses1,2. However, the molecular signals controlling Trm differentiation and homeostasis are not fully understood. Here we show that mouse Trm precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory populations at the levels of gene expression and chromatin accessibility. Exploiting computational and functional RNAi in vivo screens, we identified the transcription factor (TF) Runx3 as a key regulator of Trm differentiation and homeostasis. Runx3 was required to establish Trm populations in diverse tissue environments and supported expression of critical tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Analysis of the accessibility of Runx3 target genes in Trm-precursor cells revealed a distinct regulatory role for Runx3 in controlling Trm differentiation despite relatively widespread and uniform expression among all CD8+ T cell subsets. Further, we show that human and murine tumor-infiltrating lymphocytes (TIL) share a core tissue-residency gene-expression signature with Trm. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ TIL failed to accumulate in tumors, resulting in greater rates of tumor growth and mortality. Conversely, overexpression of Runx3 enhanced TIL abundance, delayed tumor growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of Trm differentiation, these results provide novel insight into the signals that promote T cell residency in tissues, which could be leveraged to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.
2017-12-15 | GSE107281 | GEO
Project description:Tissue-resident memory CD8+ T cells (Trm) are positioned at common sites of pathogen exposure where they elicit rapid and robust protective immune responses. However, the molecular signals controlling Trm differentiation and homeostasis are not fully understood. Here we show that mouse Trm precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory populations at the levels of gene expression and chromatin accessibility. Exploiting computational and functional RNAi in vivo screens, we identified the transcription factor (TF) Runx3 as a key regulator of Trm differentiation and homeostasis. Runx3 was required to establish Trm populations in diverse tissue environments and supported expression of critical tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Analysis of the accessibility of Runx3 target genes in Trm-precursor cells revealed a distinct regulatory role for Runx3 in controlling Trm differentiation despite relatively widespread and uniform expression among all CD8+ T cell subsets. Further, we show that human and murine tumor-infiltrating lymphocytes (TIL) share a core tissue-residency gene-expression signature with Trm. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ TIL failed to accumulate in tumors, resulting in greater rates of tumor growth and mortality. Conversely, overexpression of Runx3 enhanced TIL abundance, delayed tumor growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of Trm differentiation, these results provide novel insight into the signals that promote T cell residency in tissues, which could be leveraged to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.
2017-12-15 | GSE108092 | GEO
Project description:Tissue-resident memory CD8+ T cells (Trm) are positioned at common sites of pathogen exposure where they elicit rapid and robust protective immune responses1,2. However, the molecular signals controlling Trm differentiation and homeostasis are not fully understood. Here we show that mouse Trm precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory populations at the levels of gene expression and chromatin accessibility. Exploiting computational and functional RNAi in vivo screens, we identified the transcription factor (TF) Runx3 as a key regulator of Trm differentiation and homeostasis. Runx3 was required to establish Trm populations in diverse tissue environments and supported expression of critical tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Analysis of the accessibility of Runx3 target genes in Trm-precursor cells revealed a distinct regulatory role for Runx3 in controlling Trm differentiation despite relatively widespread and uniform expression among all CD8+ T cell subsets. Further, we show that human and murine tumor-infiltrating lymphocytes (TIL) share a core tissue-residency gene-expression signature with Trm. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ TIL failed to accumulate in tumors, resulting in greater rates of tumor growth and mortality. Conversely, overexpression of Runx3 enhanced TIL abundance, delayed tumor growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of Trm differentiation, these results provide novel insight into the signals that promote T cell residency in tissues, which could be leveraged to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.
2017-12-15 | GSE107278 | GEO
Project description:Tissue-resident memory CD8+ T cells (Trm) are positioned at common sites of pathogen exposure where they elicit rapid and robust protective immune responses. However, the molecular signals controlling Trm differentiation and homeostasis are not fully understood. Here we show that mouse Trm precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory populations at the levels of gene expression and chromatin accessibility. Exploiting computational and functional RNAi in vivo screens, we identified the transcription factor (TF) Runx3 as a key regulator of Trm differentiation and homeostasis. Runx3 was required to establish Trm populations in diverse tissue environments and supported expression of critical tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Analysis of the accessibility of Runx3 target genes in Trm-precursor cells revealed a distinct regulatory role for Runx3 in controlling Trm differentiation despite relatively widespread and uniform expression among all CD8+ T cell subsets. Further, we show that human and murine tumor-infiltrating lymphocytes (TIL) share a core tissue-residency gene-expression signature with Trm. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ TIL failed to accumulate in tumors, resulting in greater rates of tumor growth and mortality. Conversely, overexpression of Runx3 enhanced TIL abundance, delayed tumor growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of Trm differentiation, these results provide novel insight into the signals that promote T cell residency in tissues, which could be leveraged to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.
2017-12-15 | GSE107373 | GEO
Project description:Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However transcriptional heterogeneity of human intestinal TRM cells remains undefined. Here, we investigated transcriptional and functional heterogeneity of human TRM cells through study of donor-derived intestinal TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identified two distinct transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We defined a transcriptional signature discriminating these two CD8+ populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft and lymphocytes from healthy gut confirmed the two CD8+ TRM phenotypes. CD103+ CD8+ TRM cells produced IL-2, and demonstrated greater polyfunctional cytokine production, while β2-integrin+ CD69+ CD103- TRM cells had higher granzyme expression. Phenotypic and functional analysis of intestinal CD4+ T cells identified many parallels, including a distinct β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.
2020-12-05 | GSE162686 | GEO
Project description:Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However transcriptional heterogeneity of human intestinal TRM cells remains undefined. Here, we investigated transcriptional and functional heterogeneity of human TRM cells through study of donor-derived intestinal TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identified two distinct transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We defined a transcriptional signature discriminating these two CD8+ populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft and lymphocytes from healthy gut confirmed the two CD8+ TRM phenotypes. CD103+ CD8+ TRM cells produced IL-2, and demonstrated greater polyfunctional cytokine production, while β2-integrin+ CD69+ CD103- TRM cells had higher granzyme expression. Phenotypic and functional analysis of intestinal CD4+ T cells identified many parallels, including a distinct β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.
2020-12-05 | GSE162685 | GEO
Project description:CD49a marks highly cytotoxic epidermal tissue-resident memory (TRM)-cells, but their molecular circuitry and relationships to circulating populations are poorly defined. We demonstrate enrichment of RUNX family transcription factor binding motifs in human epidermal CD8+CD103+CD49a+ TRM-cells, paralleled by high RUNX2 and RUNX3 protein expression. Clonal overlap between epidermal CD8+CD103+CD49a+ TRM-cells and circulating memory CD8+CD45RA–CD62L+ T-cells identified a reservoir of circulating cells with potential to seed cytotoxic TRM-cells in new sites. Upon IL-15 and TGF-β stimulation, subsets of circulating CD8+CD45RA–CD62L+ T-cells acquired CD49a expression and cytotoxic transcriptional profiles in a RUNX2 and RUNX3 dependent manner. In contrast, knock-out of RUNX3, but not RUNX2, prevented CD103 expression. In melanoma, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8+CD103+CD49a+ TRM cell signature and overall patient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differentiation of cytotoxic CD8+CD103+CD49a+ TRM-cells, providing immunosurveillance of infected and malignant cells.
2024-04-30 | GSE232238 | GEO