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The effector program of human CD8 T cells can support tissue remodeling abilities.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Abstract Paper: CD8 T lymphocytes are classically viewed as cytotoxic T cells. Whether human CD8 T cells can, in parallel, induce a tissue regeneration program is poorly understood. Here, antigen-specific assay systems revealed that human CD8 T cells not only mediated cytotoxicity, but also promoted tissue remodeling. Activated CD8 T cells could produce the epidermal growth factor receptor (EGFR)-ligand amphiregulin (AREG) and sensitize epithelial cells for enhanced regeneration potential. Blocking the EGFR or the effector cytokines IFN-γ and TNF could inhibit tissue remodeling. This regenerative program enhanced tumor spheroid and stem-cell-mediated organoid growth. Using single-cell gene expression analysis, we identified an AREG+, tissue-resident CD8 T-cell population in healthy donor skin and adipose tissue with a strong TCR clonal relation to blood PD1+TIGIT+ CD8 T cells with tissue remodeling abilities. These findings may help to understand the complex CD8 biology in tumors and could become relevant for the design of therapeutic T-cell products.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223989 | GEO | 2023/11/20

REPOSITORIES: GEO

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The effector program of human CD8 T cells can promote both target cell killing and tissue remodeling (HaCaT)

Project description:CD8 T lymphocytes are classically viewed as cytotoxic T cells. Whether human CD8 T cells can, in parallel, induce a regenerative program is not completely understood. Here, we have studied antigen-specific assay systems, which revealed that human CD8 T cells not only mediated cytotoxicity, but also promoted bystander fibroblast and epithelial cell activation, leading to the production of tissue regenerative factors such as Amphiregulin (Areg). Tissue remodeling could be inhibited by blocking the epidermal growth factor receptor or the effector cytokines IFN- and TNF. Using single-cell chromatin accessibility and gene expression analysis, we identified a tissue-resident CD8 T cell population in healthy donor skin and adipose tissue with an effector program promoting Areg, TNF and IFNg expression, and a TCR-linkage analysis demonstrated a strong clonal relation between tissue and blood PD1+TIGIT+TOX+ CD8 T cells with tissue remodeling abilities. This regenerative program was also present in anti-cancer associated CD8 populations including chimeric antigen receptor (CAR) CD8 T cells. Once activated, the tissue regenerative program of human CD8 T cells enhanced tumor spheroid, as well as primary liver/bile duct organoid growth. Our findings may help to understand the conflicting CD8 biology in the tumor micromilieu and become relevant for the design of CD8 T-cell therapies for solid tumors.

2023-11-20 | GSE223988 | GEO

The effector program of human CD8 T cells can promote both target cell killing and tissue remodeling (MRC5)

2023-11-20 | GSE223987 | GEO

The effector program of human CD8 T cells can promote both target cell killing and tissue remodeling

Project description:CD8 T lymphocytes are classically viewed as cytotoxic T cells. Whether human CD8 T cells can, in parallel, induce a regenerative program is not understood. Here, antigen-specific assay systems revealed that human CD8 T cells not only mediated cytotoxicity, but also promoted bystander fibroblast and epithelial cell activation, leading to the production of tissue regenerative factors. Tissue remodeling by CD8 T cells could be inhibited by blocking the epidermal growth factor receptor or the effector cytokines IFN-Ã¯ÂÂ§ and TNF. The regenerative program also enhanced tumor spheroid and primary organoid growth. Using single-cell chromatin accessibility and gene expression analysis, we identified a tissue-resident CD8 T cell population in healthy donor skin and adipose tissue with a strong TCR clonal relation to blood PD1+TIGIT+ CD8 T cells with tissue remodeling abilities. Our findings may help to understand CD8 in the tumor micromilieu and become relevant for the design of CD8 T-cell therapies.

| EGAS00001006960 | EGA

Amphiregulin mediates non-cell-autonomous effect of senescence on reprogramming

Project description:Cellular senescence is an irreversible growth arrest with a highly dynamic secretome, termed the senescence-associated secretory phenotype (SASP). Senescence has been implicated in somatic reprogramming to pluripotency. The cell-intrinsic proliferation arrest is a barrier for reprogramming, whereas the SASP facilitates the cell fate conversion in nonsenescent cells. However, the mechanisms by which reprogramming-induced senescence regulates cell plasticity are not well understood. Here, we have further investigated how the heterogeneity of paracrine senescence impacts reprogramming. We show that senescence promotes in vitro reprogramming in a stress-dependent manner. We identified a catalog of SASP factors and pathways potentially involved in the cell fate conversion using an unbiased proteomic analysis. Amphiregulin (AREG), a growth factor frequently secreted by the senescent cells, promotes in vitro reprogramming by accelerating proliferation and MET via the EGFR signaling pathway. Of note, AREG treatment diminished the negative effect of donor age on reprogramming. Finally, AREG enhances in vivo reprogramming in the skeletal muscle. Hence, senescence could facilitate cellular plasticity via various SASP factors to promote reprogramming and tissue repair.

2022-07-28 | PXD028590 | Pride

Soluble SORLA enhances neurite outgrowth and regeneration through activation of EGFR and MAPK pathways

Project description:SORLA is a type I transmembrane component associated with Alzheimers disease (AD) risk. Although SORLA is abundantly expressed in neurons, physiological roles for SORLA remain yet unclear. Here, we show that cultured neurons overexpressing SORLA (SORLA TG) feature enhanced neurite length, and accelerated neurite regeneration with wounding. Enhanced accumulation of a soluble SORLA form (sSORLA) is observed in SORLA TG neurons, where purified sSORLA can sufficiently drive neurite extension and regeneration. Phosphoproteomic analysis indicates enrichment of phosphoproteins related to the EGFR/ERK pathway in SORLA TG hippocampus. We find that sSORLA can co-precipitate with EGFR in vitro, where sSORLA treatment can induce EGFR Y1173 phosphorylation in cultured neurons. sSORLA also triggers Erk activation and downstream c-fos upregulation/nuclear translocation, where pharmacological EGFR or ERK inhibition reversed enhancements in sSORLA-dependent neurite regeneration. Together, these results implicate the EGFR as a sSORLA receptor which activates ERK/c-Fos pathways to enhance neurite extension, outgrowth and regeneration.

2020-05-12 | MSV000085400 | MassIVE

Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice

Project description:Liver tumors activate a regeneration-like genetic program in surrounding liver tissue akin to the regeneration program activated by toxic liver injury. Using genetically engineered mouse models we show that this program is regulated by the Hippo pathway. Our results identify a novel mechanism of non-autonomous tumor suppression where activation of a regeneration-like program in normal cells around liver tumors caused tumor cell death and tumor regression. Strikingly, deleting YAP specifically in peritumoral hepatocytes resulted in hepatocyte death and enhanced tumor growth, while hyperactivating YAP in peritumoral hepatocytes caused the elimination of tumor cells and tumor regression.

2019-09-11 | GSE103788 | GEO

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

Project description:Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be found. Here we identified that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in Th cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that AREG-EGFR signaling induces HIF1α, which binds and transactivates IL-9, IRF4 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppress their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.

2021-06-15 | GSE163056 | GEO

Regulation of the alveolar regenerative niche by amphiregulin-producing Treg cells (10X)

Project description:This study investigates the role of regulatory T cell–derived Areg on lung regeneration following influenza infection. We use single-cell RNA sequencing to capture the heterogeneity of lung mesenchymal populations during influenza infection. Here, we probe the gene expression changes within stromal cells from wildtype mice and in mice that conditionally lack Areg from T cell sources (CD4-cre Areg-flox) at day 8 post infection with PR8/H1N1. n = 1 per genotype.

2022-12-14 | GSE169123 | GEO

Tumor-associated monocytes promote mesenchymal transformation through EGFR signaling in glioma

Project description:The role of brain immune compartments in glioma evolution remains elusive. We profiled immune cells in glioma microenvironment and the matched peripheral blood from 11 patients at a single-cell level. Notably, glioblastoma exhibits specific infiltration of certain blood-originated monocytes expressing EGFR ligands including EREG and AREG, coined as tumor-associated monocytes (TAMo). TAMo infiltration is mutually exclusive with EGFR alterations (P = 0.019), while co-occurring with mesenchymal subtype (P = 4.7x10-7) and marking worse prognosis (P = 0.004 and 0.032 in two independent cohorts). Evolutionary analysis of initial-recurrent glioma pairs and single-cell study of a multi-centric glioblastoma reveals remarkable association between elevated TAMo and glioma mesenchymal transformation. Further analysis identifies FOSL2 as a master regulator of TAMo. The roles of FOSL2-EREG/AREG-EGFR signaling axis in promoting glioma invasion were verified experimentally. Collectively, we have identified TAMo in tumor microenvironment and revealed its driving role in activating EGFR signaling to shape glioma evolution.

2023-08-01 | GSE237779 | GEO

Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells

Project description:Studies over the past decade characterized murine regulatory T cells (Tregs) with the capacity to promote tissue regeneration. In humans, such a population of tissue-repair Treg cells has not been discovered yet. Using single-cell chromatin accessibility profiles of murine and human tissue Treg cells, we defined a species-conserved and microbiota-independent repair Treg signature, with a prevailing footprint of the transcription factor BATF. Combining this signature with gene expression profiling and TCR fate mapping, we identified a population of tissue-like Treg cells in peripheral blood, characterized by the expression of BATF, CCR8 and HLA-DR. Human BATF+CCR8+ Treg cells from normal skin and adipose tissue shared features with tumor-resident Treg and tissue T-follicular helper (Tfh) cells. Inducing a Tfh-like differentiation program in naive Treg cells partially recapitulated human tissue Treg characteristics, including enhanced wound healing potential

| EGAS00001004900 | EGA

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