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Real-time quantitative PCR analysis of mouse natural killer cells isolated from the bone marrow

ABSTRACT: A large gap in our understanding of infant immunity is why natural killer (NK) cell responses are deficient, which makes infants more prone to viral infection. Here we demonstrate that transforming growth factor-beta (TGF-beta) was responsible for NK cell immaturity during infancy. We found more fully mature NK cells in CD11cdnR mice, whose NK cells lack TGF-beta receptor (TGF-beta R) signaling. Ontogenic maturation of NK cells progressed faster in the absence of TGF-beta signaling, which results in the formation of a mature NK cell pool early in life. As a consequence, infant CD11cdnR mice efficiently controlled viral infections. These data thus demonstrate an unprecedented role for TGF-beta in ontogeny that can explain why NK cell responses are deficient early in life. Bone marrow cells were isolated from CD11cdnR (TG) and wild-type (WT) mice, and NK cells were sorted at different stages of development (stages D, E, and F) using BD Biosciences FACSAria. mNK cells from stages D, E, and F were obtained from three cell sorting analyses with samples pooled from n = 12 CD11cdnR and 25 WT mice. Equal amounts of total RNA from each stage was pooled prior to gene expression analysis. RNA was prepared using the RNeasy Micro kit (Qiagen), and cDNA was obtained using the standard protocol of reverse transcription. A customized StellARay cell cycle qPCR array (Lonza) was used. Quantitative gene expression analysis (quantitative PCR) was conducted on an ABI Prism 7900 instrument (Applied Biosystems).

ORGANISM(S): Mus musculus

SUBMITTER: Yasmina Laouar

PROVIDER: E-GEOD-39511 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Real-time quantitative PCR analysis of mouse natural killer cells isolated from the bone marrow

Project description:A large gap in our understanding of infant immunity is why natural killer (NK) cell responses are deficient, which makes infants more prone to viral infection. Here we demonstrate that transforming growth factor-beta (TGF-beta) was responsible for NK cell immaturity during infancy. We found more fully mature NK cells in CD11cdnR mice, whose NK cells lack TGF-beta receptor (TGF-beta R) signaling. Ontogenic maturation of NK cells progressed faster in the absence of TGF-beta signaling, which results in the formation of a mature NK cell pool early in life. As a consequence, infant CD11cdnR mice efficiently controlled viral infections. These data thus demonstrate an unprecedented role for TGF-beta in ontogeny that can explain why NK cell responses are deficient early in life.

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Disruption of TGF-β signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells

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Cellular Mechanisms of Fatal Early-Onset Autoimmunity in Mice with the T Cell-Specific Targeting of TGFβ Receptor

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

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Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells

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Activin A and NK cell function

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Proteomic characterization of CD56posCD57 NK cell subsets

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

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Project description:<p>The mechanisms by which macrophage metabolism is regulated and the effects of metabolism on diseases remain largely unknown. We show here that TGF-β regulates the glycolysis of macrophages independently of inflammatory cytokine production, and thus affects the survival in experimental sepsis. Specifically, TGF-β increased expression and activity of phosphofructokinase-1 liver type (PFKL) in macrophages and thus promoted their glycolysis during cell activation, yet paradoxically suppressed the production of proinflammatory cytokines in the same macrophages. The upregulation of glycolysis was mediated by a mTOR-c-MYC dependent pathway, whereas the inhibition of cytokines was ascribed to the activation of SMAD3 and a downregulated activation of the pro-inflammatory transcription factors AP-1, NFkB and STAT1. Importantly, in an LPS-induced endotoxemia and CLP-sepsis models, TGF-β enhancement of macrophage glycolysis led to a decreased survival in mice, which was associated with increased blood coagulation. Analysis of cohorts of patients with sepsis and covid-19 revealed that the expression of PFKL, TGF-β receptor TGFBRI and coagulation factor F13A1 in myeloid cells positively correlated with the progression of the disease. Thus, TGF-β is emerging as a critical cytokine regulating macrophage metabolism and could serve as a therapeutic target in patients with sepsis.</p>

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