The transcription factor Tcf1 ensures the development and cytotoxic function of NK cells by limiting the expression of Granzymes
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PROVIDER: PRJNA358406 | ENA |
REPOSITORIES: ENA
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Project description:The transcription factor Tcf1 plays an essential role for the development of NK cells, however, its precise role for NK cell development, maturation and function is poorly understood. Here we show that distinct domains of Tcf1 direct bone marrow progenitors towards the NK cell lineage and mediate lineage commitment and NK cell expansion, and that Tcf1 downregulation is required for terminal NK cell maturation. Impaired NK cell development in the absence of Tcf1 is explained by increased cell death due to excessive expression of Granzyme family proteins, which results in NK cell self-destruction. In addition, excessive Granzyme B expression leads to target cell induced NK cell death and consequently reduced target cell killing by NK cells lacking Tcf1. Mechanistically, Tcf1 prevents excessive Granzyme B expression by binding to a newly identified enhancer element upstream of the Granzyme B locus. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for lymphocyte development.
2017-08-23 | GSE92709 | GEO
Project description:The transcription factor Tcf1 plays an essential role for the development of NK cells, however, its precise role for NK cell development, maturation and function is poorly understood. Here we show that distinct domains of Tcf1 direct bone marrow progenitors towards the NK cell lineage and mediate lineage commitment and NK cell expansion, and that Tcf1 downregulation is required for terminal NK cell maturation. Impaired NK cell development in the absence of Tcf1 is explained by increased cell death due to excessive expression of Granzyme family proteins, which results in NK cell self-destruction. In addition, excessive Granzyme B expression leads to target cell induced NK cell death and consequently reduced target cell killing by NK cells lacking Tcf1. Mechanistically, Tcf1 prevents excessive Granzyme B expression by binding to a newly identified enhancer element upstream of the Granzyme B locus. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for lymphocyte development.
2017-08-23 | GSE92710 | GEO
Project description:Single-cell transcriptomics was performed to investigate the bone marrow NK cell compartment of myeloma patients at diagnosis (n=19), during treatment (n=21) and at relapse (n=6). The bone marrow of myeloma patients is characterized by a reduction in conventional cytotoxic NK cells that persists throughout treatment. We show in 20% of newly diagnosed myeloma patients that an altered balance between cytotoxic and cytokine-producing NK cells translates into a reduced cytotoxic ability in response to therapeutic antibodies. The relative loss of cytotoxic NK cells persists at relapse and is accompanied by an expansion of IFN-responsive NK cells. These findings reveal previously unappreciated alterations in bone marrow NK cell composition and highlight the importance of understanding the bone marrow immune system in patients receiving immunotherapies.
2023-07-18 | E-MTAB-13157 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-08-23 | GSE92711 | GEO
Project description:Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. Mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated. The transcriptional repressor BACH2 plays a critical role within the adaptive immune system, but its function within innate lymphocytes has been unclear. Here, we show that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function. BACH2 is expressed within developing and mature NK cells and promotes the maintenance of immature NK cells by restricting their maturation in the presence of weak stimulatory signals. Loss of BACH2 within NK cells results in accumulation of activated NK cells with unrestrained cytotoxic function within tissues, which mediate augmented immune surveillance to pulmonary cancer metastasis. These findings establish a critical function of BACH2 as a global negative regulator of innate cytotoxic function and tumor immune surveillance by NK cells.
2022-09-27 | GSE214128 | GEO
Project description:The transcription factor Tcf1 ensures the development and cytotoxic function of NK cells by limiting the expression of Granzymes [Affymetrix]
| PRJNA358407 | ENA
Project description:The transcription factor Tcf1 ensures the development and cytotoxic function of NK cells by limiting the expression of Granzymes [ChIP-Seq]
| PRJNA358408 | ENA
Project description:NK cells are lymphocytes that provide a first defense against viral infections and cancer. They act (i) cytotoxic by killing virus-infected and tumorigenic cells and (ii) immune regulatory by releasing cytokines and chemokines. These innate immune cells are commonly further classified as CD56bright and CD56dim NK cells. Former studies confirmed immune regulatory CD56bright NK cells as progenitors of cytotoxic CD56dim NK cells. CD57 was previously described as T cell marker for senescence and terminal differentiation. Recent studies detected CD57+ and CD57- NK cells among the CD56dim NK cell population and suggested a fully mature developmental status for CD57+ NK cells. The recent NK cell maturation model includes CD34+ hematopoietic stem cells (HSC), which develop into CD56bright NK cells, later into CD56dimCD57- and finally into terminally maturated CD56dimCD57+ (1) (2) (3). The molecular mechanisms of human NK cell differentiation and maturation remain unknown to this date. We performed for the first time a proteomic analysis of these distinct developmental stages of human primary NK cells, isolated from overall 10 healthy human blood donors. CD56bright NK cells versusCD56dim and CD56dimCD57- versus CD56dimCD57+ NK cells were analyzed by using quantitative peptide sequencing, which revealed individual protein signatures (3400 proteins) of these different NK cell developmental stages. Notably, our data support the current NK cell differentiation model by highlighting both strong distinctions between CD56dim/bright NK cells and close relationships between CD57+/- NK cells on the proteomic level. Among the most prominent and conserved regulated proteins, we detected myosin IIa, Calvasculin and Calcyclin with very similar expression patterns. We investigated their sub-cellular localization and observed specific recruitment- and accumulation-events at the NK cell immunological synapse (NKIS) after NK activation.
2013-01-23 | PRD000666 | Pride
Project description:Natural killer (NK) cells are a type of innate lymphocytes that play key roles in immune surveillance against tumors and viral infection. NK cells distinguish abnormal cells from healthy cells by cell-cell interaction with cell surface proteins and then attack target cells via multiple mechanisms involving TRAIL, Fas Ligand, cytokine secretion, perforin, and granzymes. In addition, extracellular vesicles (EVs), including exosomes derived from NK cells (NK-EVs), possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines remain unknown. Here, we report that EVs derived from human NK-92 cells stimulated with IL-15 + IL-21 show enhanced cytotoxic capacity against tumor cells in a granzyme B independent manner. In addition, small RNA-seq and mass spectrometry analyses indicate that miRNA and protein profiles in EVs are altered by cytokine stimulation. We also show NK-EVs are taken up by target cells via macropinocytosis. Collectively, our findings reveal novel characteristics of NK-EVs and the mechanism of their incorporation into target cells.
2021-09-09 | PXD018982 | Pride
Project description:Human ILCs are classically categorized into five subsets; cytotoxic CD127-CD94+ NK cells and non-cytotoxic CD127+CD94-, ILC1s, ILC2s, ILC3s and LTi cells. Here, we identify a novel subset within the CD127+ ILC population, characterized by the expression of the cytotoxic marker CD94. These CD94+ ILCs strongly resemble conventional ILC3s in terms of phenotype, transcriptome and cytokine production, but are highly cytotoxic. IL-15 was unable to induce differentiation of CD94+ ILCs towards mature NK cells. Instead, CD94+ ILCs retained RORγt, CD127 and CD200R expression and produced IL-22 in response to IL-15. Culturing non-cytotoxic CD127+ ILC1s or ILC3s with IL-12 induced upregulation of CD94 and cytotoxic activity, effects that were not observed with IL-15 stimulation. Thus, human helper ILCs can acquire a cytotoxic program without differentiating into NK cells.
2020-09-14 | GSE147231 | GEO