FTO negatively regulates the cytotoxic activity of natural killer cells
Ontology highlight
ABSTRACT:
SUBMITTER: Seok-Min Kim
PROVIDER: S-SCDT-10_15252-EMBR_202255681 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Bach2 has been reported to regulate multiple immune cell development and function. Here we report that Bach2 is constitutively expressed in relatively immature NK subsets. Bach2 negatively regulates NK cell development and Bach2 deficiency results in NK cell with mature effector phenotype. Thus, Bach2 functions as a negative regulator of NK cell maturation and function.
2022-02-10 | GSE196530 | GEO
Project description:Ex vivo differentiation systems of natural killer (NK) cells from CD34+ hematopoietic stem cells are of potential importance for adjuvant immunotherapy of cancer. Here, we analyzed ex vivo differentiation of NK cells from cord blood-derived CD34+ stem cells by gene expression profiling, real-time RT-PCR, flow cytometry, and functional analysis. Additionally, we compared the identified characteristics to peripheral blood (PB) CD56(bright) and CD56(dim) NK cells. The data show sequential expression of CD56 and the CD94 and NKG2 receptor chains during ex vivo NK cell development, resulting finally in the expression of a range of genes with partial characteristics of CD56(bright) and CD56(dim) NK cells from PB. Expression of characteristic NK cell receptors and cytotoxic genes was mainly found within the predominant ex vivo generated population of NKG2A+ NK cells, indicating the importance of NKG2A expression during NK cell differentiation and maturation. Furthermore, despite distinct phenotypic characteristics, the detailed analysis of cytolytic genes expressed within the ex vivo differentiated NK cells revealed a pattern close to CD56(dim) NK cells. In line with this finding, ex vivo generated NK cells displayed potent cytotoxicity. This supports that the ex vivo differentiation system faithfully reproduces major steps of the differentiation of NK cells from their progenitors, constitutes an excellent model to study NK cell differentiation, and is valuable to generate large-scale NK cells appropriate for immunotherapy.
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Project description:Natural killer (NK) cells have been shown to mediate important immunoregulatory "helper" functions in addition to their cytolytic activity. In particular, NK cells are capable of preventing maturation-related dendritic cell (DC) "exhaustion," inducing the development of "type-1 polarized" mature DCs (DC1) with an enhanced ability to produce interleukin (IL)-12p70, a factor essential for type-1 immunity and effective anticancer responses. Here we show that the NK cell-mediated type-1 polarization of DCs can be applied in the context of patients with advanced cancer to enhance the efficacy of DCs in inducing tumor-specific cytotoxic T lymphocytes. NK cells isolated from patients with late-stage (stage III and IV) melanoma responded with high interferon-? production and the induction of type-1-polarized DCs on exposure to defined combinations of stimulatory agents, including interferon-? and IL-18. The resulting DCs showed strongly-enhanced IL-12p70 production on subsequent T-cell interaction compared with immature DCs (average of 19-fold enhancement) and nonpolarized IL-1?/TNF-?/IL-6/PGE(2)-matured "standard" DCs (average of 215-fold enhancement). Additional inclusion of polyinosinic: polycytidylic acid during NK-DC cocultures optimized the expression of CD80, CD86, CD40, and HLA-DR on the resulting (NK)DC1, increased their CCR7-mediated migratory responsiveness to the lymph node-associated chemokine CCL21, and further enhanced their IL-12-producing capacity. When compared in vitro with immature DCs and nonpolarized standard DCs, (NK)DC1 were superior in inducing functional melanoma-specific cytotoxic T lymphocytes capable of recognizing multiple melanoma-associated antigens and killing melanoma cells. These results indicate that the helper function of NK cells can be used in clinical settings to improve the effectiveness of DC-based cancer vaccines.
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Project description:While the invariant natural killer T (iNKT)-cell response to primary stimulation with the glycolipid, ?-galactosylceramide (?GalCer), is robust, the secondary response to this stimulus is muted resulting in a hyporesponsive state characterized by anti-inflammatory interleukin-10 (IL-10) production and high expression of programmed cell death 1 (PD1) and neuropilin 1 (NRP1). The E protein transcription factors and their negative regulators, the Id proteins, have previously been shown to regulate iNKT cell thymic development, subset differentiation and peripheral survival. Here, we provide evidence that the expression of the transcriptional regulator Id2 is downregulated upon stimulation of iNKT cells with their cognate antigen. Moreover, loss of Id2 expression by iNKT cells resulted in a hyporesponsive state, with splenic Id2-deficient iNKT cells expressing low levels of TBET, high levels of PD1 and NRP1 and production of IL-10 upon stimulation. We propose that downregulation of Id2 expression is an essential component of induction of the anti-inflammatory, hyporesponsive state in iNKT cells.
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Project description:BackgroundPMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder.ObjectiveTo evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors.MethodsWe studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay.ResultsWe found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules.ConclusionsOur results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present work improves our understanding of the immunological functions in PMM2-CDG and possibly in other CDG-I types.
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Project description:Natural killer (NK) cells derived or isolated from different sources have been gaining in importance for cancer therapies. In this study, we evaluate and compare key characteristics between NK cells derived or isolated from umbilical cord blood, umbilical cord blood hematopoietic stem/progenitor cells, peripheral blood, and induced pluripotent stem cells (iPSCs). Specifically, we find CD56+ NK cells isolated and expanded directly from umbilical cord blood (UCB56) and NK cells derived from CD34+ hematopoietic stem/progenitors in umbilical cord blood (UCB34) differ in their expression of markers associated with differentiation including CD16, CD2, and killer Ig-like receptors (KIRs). UCB56-NK cells also displayed a more potent cytotoxicity compared to UCB34-NK cells. NK cells derived from iPSCs (iPSC-NK cells) were found to have variable KIR expression, with certain iPSC-NK cell populations expressing high levels of KIRs and others not expressing KIRs. Notably, KIR expression on UCB56 and iPSC-NK cells had limited effect on cytotoxic activity when stimulated by tumor target cells that express high levels of cognate HLA class I, suggesting that in vitro differentiation and expansion may override the KIR-HLA class I mediated inhibition when used across HLA barriers. Together our results give a better understanding of the cell surface receptor, transcriptional, and functional differences between NK cells present in umbilical cord blood and hematopoietic progenitor-derived NK cells which may prove important in selecting the most active NK cell populations for treatment of cancer or other therapies.
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