Epigenetic control of CD8+ T cell tissue resident memory precursors differentiation by the histone methyltransferase SUV39H1 [Multiomics]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE308693 | GEO | 2026/09/14
REPOSITORIES: GEO
Similar Datasets
Project description:The molecular mechanisms of fate choices between circulatory and tissue-resident memory (TRM) cells upon CD8+ T cell activation, are still largely unknown. We show here that deletion of the histone methyltransferase SUV39H1 in CD8+ T cells, enhances homing to non-lymphoid tissues. At steady state, after space-induced proliferation or flu infection, SUV39H1-defective cells in tissues express CD49d and differentiate predominantly into CD69+/CD103- TRM. Persisting SUV39H1-defective T cells in lungs are protective in flu re-infection and lung tumor models. Accumulation of SUV39H1-deficient TRM cells is due to increased proportions of TRM precursors with high stemness and TRM precursor potential. We conclude that SUV39H1 restrains CD69+ CD103- TRM commitment by inhibiting memory and stemness programs during CD8+ T cells effector differentiation. These results encourage the use of SUV39H1 depletion in the context of adoptive T cell therapies to optimize both the efficiency of target cell eradication and the long-term persistence of memory cells.
2026-09-14 | GSE308060 | GEO
Project description:Tumor infiltrating lymphocytes (TIL) with a CD8+ T cell tissue-resident memory (Trm) phenotype are associated with improved patient outcomes in solid malignancies. To define programs governing the formation of Trm-like TIL, we performed paired single-cell RNA sequencing and single-cell ATAC sequencing of T cell receptor (TCR)-matched CD8+ T cells in models of infection and cancer. Enhancer-driven regulons assembled from multiomic profiling data revealed epigenetic and transcriptional programs regulating the formation of Trm-like TIL in relation to canonical exhausted and memory T cell states. The transcriptional regulator KLF2 repressed the formation of CD69+CD103+ Trm-like TIL and limited anti-tumor activity. Conversely, sustained expression of the transcription factor BATF enhanced formation of CD69+CD103+ TIL, contingent upon downregulation of KLF2. Transforming growth factor β (TGF-β) signaling and CD103 expression were necessary for Trm-like TIL formation, but BATF overexpression was sufficient to drive formation of CD69+CD103+ TIL in TGFBR2-silenced cells. These findings reveal mechanisms of Trm-like TIL differentiation and provide a framework for considering tissue residency in the context of CD8+ T cell heterogeneity in the tumor microenvironment.
2025-05-26 | GSE267584 | GEO
Project description:Tumor infiltrating lymphocytes (TIL) with a CD8+ T cell tissue-resident memory (Trm) phenotype are associated with improved patient outcomes in solid malignancies. To define programs governing the formation of Trm-like TIL, we performed paired single-cell RNA sequencing and single-cell ATAC sequencing of T cell receptor (TCR)-matched CD8+ T cells in models of infection and cancer. Enhancer-driven regulons assembled from multiomic profiling data revealed epigenetic and transcriptional programs regulating the formation of Trm-like TIL in relation to canonical exhausted and memory T cell states. The transcriptional regulator KLF2 repressed the formation of CD69+CD103+ Trm-like TIL and limited anti-tumor activity. Conversely, sustained expression of the transcription factor BATF enhanced formation of CD69+CD103+ TIL, contingent upon downregulation of KLF2. Transforming growth factor β (TGF-β) signaling and CD103 expression were necessary for Trm-like TIL formation, but BATF overexpression was sufficient to drive formation of CD69+CD103+ TIL in TGFBR2-silenced cells. These findings reveal mechanisms of Trm-like TIL differentiation and provide a framework for considering tissue residency in the context of CD8+ T cell heterogeneity in the tumor microenvironment.
2025-05-26 | GSE290081 | GEO
Project description:Tissue-resident memory T cells (TRM) persist locally in non-lymphoid tissues where they provide front-line defense against recurring insults. TRM at barrier surfaces express the markers CD103 and/or CD69 which function to retain them in epithelial tissues. In humans, neither the long-term migratory behavior of TRM nor their ability to re-enter the circulation and potentially migrate to distant tissue sites have been investigated. Using tissue explant cultures, we found that CD4+CD69+CD103+ TRM in human skin can downregulate CD69 and exit the tissue. Additionally, we identified a skin-tropic CD4+CD69-CD103+ population in human lymph and blood that is transcriptionally, functionally and clonally related to the CD4+CD69+CD103+ TRM population in the skin. Using a skin xenograft model, we confirmed that a fraction of the human cutaneous CD4+CD103+ TRM population can re-enter circulation, and migrate to secondary human skin sites where they re-assume a TRM phenotype. Thus, our data challenge current concepts regarding the strict tissue compartmentalization of CD4+ T cell memory in humans.
2019-05-25 | GSE131770 | GEO
Project description:Tissue resident memory (Trm) represent a newly described memory T cell population. We have previously characterized a population of Trm that persists within the brain following acute virus infection. Although capable of providing marked protection against a subsequent local challenge, brain Trm do not undergo recall expansion following dissociation from the tissue. Furthermore, these Trm do not depend on the same survival factors as the circulating memory T cell pool as assessed either in vivo or in vitro. To gain greater insight into this population of cells we compared the gene-expression profiles of Trm isolated from the brain to circulating memory T cells isolated from the spleen following an acute virus infection. Trm displayed altered expression of genes involved in chemotaxis, expressed a distinct set of transcription factors and overexpressed several inhibitory receptors. Cumulatively, these data indicates that Trm are a distinct memory T cell population disconnected from the circulating memory T cell pool and displaying a unique molecular signature which likely results in optimal survival and function within their local environment. 13 samples were analyzed: 5 replicates of memory OT-I CD8+.CD103- T cells isolated from the spleen of mice on day 20 p.i. with VSV-OVA. 5 replicates of memory OT-I CD8+CD103+ T cells isolated from the brain of mice on day 20 p.i. with VSV-OVA; and 3 replicates of memory OT-I.CD8+ CD103- T cells isolated from the brain of mice on day 20 p.i. with VSV-OVA
2012-08-29 | E-GEOD-39152 | biostudies-arrayexpress
Project description:Current cancer immunotherapies promote recovery of CD103+ tissue-resident memory T cells (Trm) population of the tumor-infiltrating T lymphocytes (TILs). However, not all treated patients exhibit improved anti-tumor immunity and survival, likely due to the immunophenotypical diversity among the CD103+ Trm TILs. Utilising multifaceted proteomics approaches and patients’ clinical analyses, we discovered an unusual subset of CD8+ Trm TILs expressing non-canonical integrin β3 early during T cells activation. The integrin β3 surprisingly heterodimerises with CD103 on T cells, leading to unconventional granulysin-mediated cytotoxicity, elevated alternative bioenergy usage and efficient T cell migration, with minimal overall exhaustion. Importantly, early-stage non-small cell lung carcinoma (NSCLC) patients with enriched presence of integrin β3+CD103+ Trm TILs exhibited better clinical prognosis, with improved T cell immunophenotype, hence confirming the beneficial role of this unusual subset of Trm TILs. These unconventional anti-tumor T cell features provide new avenues and future opportunities for designing better translational immunotherapy strategies.
2024-02-14 | PXD031794 | Pride
Project description:A specialized population of memory CD8+ T-cells resides in the epithelium of the respiratory tract to maintain protection against recurring infections. These cells express CD69 and the integrin αβ7 (CD103) and correspond to tissue resident memory T-cells (TRM) also described in intestine, liver and brain. A less well characterized population of CD103- CD8+ T-cells also resides in lungs and expresses markers characteristic of effector memory T-cells (TEM). We determined the transcriptional profiles of these memory CD8+ T-cell subsets retrieved from human lung resection samples and compared these with corresponding T-cell populations from peripheral blood of the same individuals. Our results demonstrate that each of the populations exhibits a distinct transcriptional identity. We found that the lung environment has a major impact on gene expression profiles. Thus, transcriptomes from CD103+ and CD103- subsets from lungs are much more resemblant to one another than to those from CD103+ or CD103- memory CD8+ T-cells from blood. TRM express specific sets of chemokine receptors, in accordance with their unique migratory properties. Furthermore, these cells constitutively express cytokine and cytotoxic genes for immediate effector function and chemokines to attract auxiliary immune cells. At the same time, multiple genes encoding inhibitory regulators are also expressed. This suggests that rapid ability to unleash effector functions is counterbalanced by programmed restraint, a combination that may be critical in the exposed but delicate tissue of the lung. Comprehensive sets of transcription factors were identified that characterize the memory CD8+ populations in the lungs. Prominent among these were components of the Notch pathway. Using mice genetically lacking expression of the NOTCH1 and NOTCH2 receptors in T-cells, we demonstrated that Notch controls both the number of lung TRM as well as the function of lung TEM. Our data illustrate the adaptation of lung resident T-cells to the requirements of the respiratory epithelial environment. Defining the molecular imprinting of these cells is important for rational vaccine design and may help to improve the properties of T-cells for adoptive cellular therapy. Material was collected from a total of 6 subjects. Three patients underwent a lobectomy for a peripheral primary lung tumor and three received lung transplantation because of end-stage pulmonary disease (COPD). Lung mononuclear cells where isolated after digestion of the partial or complete human lung resection material. Paired peripheral blood mononuclear cells were also isolated. CD8+CD16-CD56- T-cells were sorted for expression of CD103 (ITGAE). Lung and blood derived CD103+ and CD103- T-cell fractions were directly lysed after FACS sorting or stimulated overnight with antiCD3/28 beads. Due to the low frequency of resting (non-stimulated) CD103+ T-cells in peripheral blood this subset was obtained from five non-related buffy coat donors. RNA was isolated from 36 sorted cell samples and hybridized on Illumina HumanHT-12 V4.0 microarrays. Eight microarray samples (including two samples from the buffy coat donors) were excluded after hybridization since their average signal was too low.
2016-10-23 | E-GEOD-61397 | biostudies-arrayexpress
Project description:Resident memory T (TRM) cells have been recently established as an important subset of memory cells that provide early and essential protection against reinfection in the absence of circulating memory T cells. Recent findings showing that TRM expand in vivo after repeated antigenic stimulation indicate that these memory T cells are not terminally differentiated. This suggest an opportunity for in vitro TRM expansion to apply in an immunotherapy setting. However, it has also been shown that TRM may not maintain their identity and form circulating memory T cells after in vivo restimulation. Therefore, we set out to determine how TRM respond to antigenic activation in culture. Using Listeria monocytogenes and LCMV infection models, we found that TRM from the intraepithelial compartment of the small intestine expand in vitro after antigenic stimulation and subsequent resting in homeostatic cytokines. A large fraction of the expanded TRM retained their phenotype, including the expression of key TRM markers CD69 and CD103 (ITGAE). Optimal culture of TRM required low O2 pressure to maintain the expression of these and other TRM associated molecules. Expanded TRM retained their effector capacity to produce cytokines after restimulation, but did not acquire a highly glycolytic profile indicative of effector T cells. Proteomic analysis confirmed TRM profile retention, including expression of TRM-related transcription factors, tissue retention factors, adhesion molecules and enzymes involved in fatty acid metabolism. Collectively, our data indicate that limiting oxygen conditions support in vitro expansion of TRM cells that maintain their TRM phenotype, at least in part, suggesting an opportunity for therapeutic strategies that require in vitro expansion of TRM.
2025-09-30 | PXD041211 | Pride
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