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Natural Killer Cell Plasticity During IL-15-driven Homeostatic Proliferation

ABSTRACT: Here we performed single-cell RNA sequencing to address repertoire stability and subset plasticity during IL-15 driven homeostatic proliferation. Sorted NK cell subsets representing discrete stages of NK cell differentiation are compared with the corresponding subsets after proliferation and further sorted into two subsets depending on the rate of proliferation.

PROVIDER: EGAS00001003946 | EGA |

REPOSITORIES: EGA

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e6e86f78-8562-444b-a561-de8315ee7cf9 - samples

Project description:Here we performed single-cell RNA sequencing to address repertoire stability and subset plasticity during IL-15 driven homeostatic proliferation. Sorted NK cell subsets representing discrete stages of NK cell differentiation are compared with the corresponding subsets after proliferation and further sorted into two subsets depending on the rate of proliferation.

| EGAD00001005420 | EGA

TNFα/TNFR2 axis mediates natural killer cell proliferation by enhancing their glycolytic plasticity

Project description:Natural Killer (NK) cells are predominant innate lymphocytes that provide the early response during infection. NK cells undergo metabolic switch to fuel augmented proliferation and activation following infection. TNFα is a well-known inammatory cytokine that enhances NK cell function, however, a mechanism for stimulation is not well established. Here, we demonstrated that upon infection/inammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity and effector function. Notably, IL-18 can induce TNFR2 on NK cells, augmenting their sensitivity towards TNFα. Mechanistically, TNFα-TNFR2 signaling induces CD25 (IL-2Rα) expression on NK cells predominantly by autocrine mode, leading to a metabolic switch towards aerobic glycolysis. Accordingly, genetic ablation of TNFR2 curtails the CD25 upregulation and TNFα-induced glycolysis, leading to impaired NK cell proliferation during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFα-TNFR2 axis in NK cells for proliferation, glycolysis, and effector function via CD25 induction.

2023-09-26 | GSE235545 | GEO

Transcriptional Reference Map of Human Natural Killler Cells

Project description:The functional diversity of NK cell repertoires stems from differentiation, homeostatic receptor-ligand interactions, and adaptive-like responses to viral infections. Here we performed single-cell RNA sequencing of both bulk NK and sorted NK subsets to establish a transcriptional reference map of human natural killer cells based on single-cell RNA sequencing profiles from 72,129 cells obtained from bulk (12 donors) and sorted phenotypically-defined NK cell subsets (2 donors) and tissue-resident NK cells (TrNK, 136 donors). Our own data is included here.

2023-10-27 | GSE245690 | GEO

Transcription profiling by array of human CD56brightCD16-, CD56dimNKG2A+ and CD56dimNKG2A- natural killer cell subsets

Project description:CD56brightCD16-, CD56dimNKG2A+ and CD56dimNKG2A- NK cells subsets were FACS sorted and their transcriptional profile were compared after whole genome microarray analysis.

2010-08-10 | E-MEXP-2798 | biostudies-arrayexpress

Core fucosylation of IL-15 receptor delineates homeostatic proliferation and apoptosis signalling required for natural killer cell development

Project description:Natural Killer (NK) cell development and effector function requires context-dependent signalling via numerous receptors including the IL-15 receptor. The modulation of receptor signalling can be regulated by the post-translational modifications affecting receptor turnover and trafficking. Core fucosylation is one such modification known to impact receptor expression and is uniquely mediated by fucosyltransferase 8 (FUT8). To investigate core fucosylation in NK cell biology, we generated mice lacking FUT8 in NK cells (Fut8fl/flNcr1cre/+). Loss of core fucose resulted in pronounced NK lymphopenia in Fut8fl/flNcr1cre/+ mice associated with a reduction in IL-15 receptor expression and loss of in vivo proliferation. Inhibition of intrinsic apoptosis pathways could not overcome compromised IL-15 receptor signalling to rescue FUT8-null NK cell development delineating the contribution of proliferation to NK cell homeostasis. Surprisingly, loss of core fucose enhanced NK cell expansion following viral infection and this was associated with upregulation of IL-2Rα following pro-inflammatory cytokine exposure and enhanced IL-2-mediated proliferation. Lastly, loss of FUT8 activity impaired TGFBR2 expression and immunosuppressive effects of TGF-β on NK cells. Taken together, we have identified fucosyltransferase 8 as a key modulator of NK cell development and function by regulating IL-15 receptor responsiveness.

2024-01-01 | GSE243190 | GEO

Xbp1s controls IL-15-mediated natural killer cell survival and function by regulating Pim2 and Tbet

Project description:We previously reported that X-Box Binding Protein 1 (Xbp1s), an essential transcriptional factor downstream of IL-15 and Akt signaling, controls cell survival and effector function in human natural killer (NK) cells. However, the mechanisms by which Xbp1s regulates NK cell survival and function remains unknown. In this study, by using Xbp1s conditional knock-out (KO) mice, we found that Xbp1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanically, Xbp1s regulates homeostatic NK cell survival through targeting Pim2, a critical anti-apoptotic gene. Pim2 in turn stabilizes Xbp1s protein through phosphorylation at Thr58. Xbp1s enhances NK cell effector function and anti-tumor immunity via recruitment of Tbet to the promoter region of Ifng. Collectively, our findings reveal an important role of IL-15–Xbp1s signaling in NK cell survival and effector function.

2022-12-31 | GSE188796 | GEO

Transcription profiling of mouse natural killer (NK) cell subsets defined by CD27 and CD11b expression

Project description:Previous reports have defined three subsets of mouse NK cells on the basis of the expression of CD27 and CD11b. The developmental relationship between these subsets was unclear. To address this issue, we evaluated the overall proximity between mouse NK cell subsets defined by CD27 and CD11b expression using pangenomic gene expression profiling. The results suggest that CD27+CD11b-, CD27+CD11b+ and CD27-CD11b+ correspond to three different intermediates stages of NK cell development. Experiment Overall Design: Spleen cells from RAG-/- mice have been isolated and stained with anti-NK1.1, anti CD27 and anti CD11b antibodies. NK1.1+ cells were sorted into CD27+ CD11b-, CD27+ CD11b+ and CD27- CD11b+ subsets by flow cytometry. There are two independent replicates for each sample. Total RNA was extracted with the RNeasy microkit (Qiagen) and gene expression profiles were performed according to manufacturer instructions (Affymetrix mouse 430 2.0).

2009-03-21 | E-GEOD-13229 | biostudies-arrayexpress

Natural Killer Cell Plasticity During IL-15-driven Homeostatic Proliferation

Project description:Data Access Committee EGAC00001001346

| EGAC00001001346 | EGA

An XBP1s-PIM-2 positive feedback loop controls IL-15-mediated survival of natural killer cells

Project description:We previously reported that XBP1s, an essential transcription factor downstream of IL-15 and AKT signaling, controls cell survival and effector functions of human natural killer (NK) cells. However, the precise mechanisms remain unknown. In this study, by using XBP1 conditional knock-out mice, we found that XBP1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanistically, XBP1s regulates homeostatic NK cell survival through targeting PIM-2, a critical anti-apoptotic gene, which in turn stabilizes XBP1s protein by phosphorylating it at Thr58. In addition, XBP1s enhances the effector functions and anti-tumor immunity of NK cells by recruiting T-bet to the promoter region of Ifng. Collectively, our findings identify a previously unknown mechanism by which IL-15–XBP1s signaling regulates the survival and effector functions of NK cells.

2022-12-31 | GSE218543 | GEO

Transcription profiling of mouse resting and IL-15 activated natural killer cells

Project description:Murine NK cells were compared at rest and following 24 hours of IL-15 stimulation for their mRNA expression profiles on the Affymetrix MOE430_2 microarray platform. Additional comparators included resting bulk splenocytes. Experiment Overall Design: Three pairs of flow sorted murine NK cells (C57Bl/6) were analzyed at rest or after 24 hours of IL-15 stimulation. Three biological replicates of each condition (resting or IL-15) are included in this anlaysis. In addition, bulk resting splenocytes were used (2 biological replicates with 2 chip replicates for a total of 4 replicates).

2009-04-28 | E-GEOD-7764 | biostudies-arrayexpress

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