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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.

2012-07-25 | GSE39511 | GEO

Autocrine TGF-β1 drives tissue-specific differentiation and function of resident NK cells

Project description:Group 1 innate lymphoid cells (ILCs) encompass NK cells and ILC1s which have non-redundant roles in host protection against pathogens and cancer. Despite their circulating nature, NK cells can establish residency in selected tissues during ontogeny, forming a distinct functional subset. The mechanisms that initiate, maintain, and regulate the conversion of NK cells into tissue-resident NK (trNK) cells are currently not well understood. Here, we identify autocrine transforming growth factor-b (TGF-b) as a cell-autonomous driver for NK cell tissue-residency across multiple glandular tissues during development. Cell-intrinsic production of TGF-β was continuously required for the maintenance of trNK cells and synergized with Hobit to enhance cytotoxic function. Whereas autocrine TGF-β was redundant in tumors, our study revealed that NK cell-derived TGF-β allowed expansion of cytotoxic trNK cells during local infection with murine cytomegalovirus (MCMV) and contributed to viral control in the salivary gland. Collectively, our findings reveal tissue-specific regulation of trNK cell differentiation and function by autocrine TGF-β1, which is relevant for anti-viral immunity.

2024-11-21 | GSE282148 | GEO

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

Project description:Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF-β) is highly expressed in the liver tumor microenvironment and is known to inhibit immune cell activity. Here, we used human iPSCs to produce natural killer (NK) cells engineered to mediate improved anti-HCC activity. Specifically, we produced iPSC-NK cells with either knock out TGF-β receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-β receptor 2 (TGFBR2-DN) combined with CARs that target either GPC3 or AFP. The TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-β inhibition and improved anti-HCC activity. However, expression of anti-HCC CARs on iPSC-NK cells did not lead to effective anti-HCC activity unless there was also inhibition of TGF-b activity. Our findings demonstrate that TGF-β signaling blockade is required for effective NK cell function against HCC and potentially other malignancies which express high levels of TGF-β.

2024-04-08 | GSE263459 | GEO

CD137 costimulation counteracts TGFβ inhibition of NK cell anti-tumor function and promotes the acquisition of tissue-resident Th9-like properties [4 treatments]

Project description:Enhancing NK cell-based cancer immunotherapy by overcoming immunosuppression is an unmet goal. Here, we demonstrate the ability of the anti-CD137 agonist urelumab for overcoming TGF-β-mediated inhibition of human NK-cell proliferation and sustained anti-tumor function. Transcriptomic, immunophenotypic and functional analyses evidenced that CD137 costimulation modified the transcriptional program induced by TGF-β on activated NK cells by limiting SMAD4-dependent inhibition of pro-proliferative (CD25, cMyc), activating (NKG2D, CD16) and effector (Granzyme B, IFNγ) molecules while maintaining SMAD4-independent acquisition of tumor-retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGF-β1 and CD137 agonist showed preserved antibody-dependent cytotoxicity against cancer cells, recovered CCL5 and IFNγ secretion and gained the capacity for producing IL-9 upon restimulation. Treatment of breast tumor-derived multicellular cultures with trastuzumab and urelumab recapitulated CD137 induction and fostered tumor-infiltrating CD16+ NK cell persistence. Our data reveals CD137 as a targetable checkpoint for overturning TGF-β constrains on NK cell anti-tumor responses.

2021-09-10 | GSE143375 | GEO

CD137 costimulation counteracts TGFβ inhibition of NK cell anti-tumor function and promotes the acquisition of tissue-resident Th9-like properties [2 treatments]

2021-09-10 | GSE156199 | GEO

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

Project description:Transforming growth factor-β (TGF-β) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF-β in the control of immune homeostasis is not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF-β signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions with 100% mortality. Peripheral CD4+ and CD8+ T cells with TGF-β-receptor II (TGF-βRII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-βRII deficiency blocked the development of canonical CD1d-restricted NKT cells. Instead, it facilitated generation of a highly pathogenic T cell subset exhibiting multiple hallmarks of NK cells and sharply elevated amounts of FasL, perforin, granzymes, and interferon-γ. Thus, TGF-β signaling in peripheral T cells is crucial in restraining TCR activation-dependent Th1, cytotoxic, and NK cell-like differentiation program which, when left unchecked, leads to rapidly progressing fatal autoimmunity. Keywords: Cell type comparison

2006-10-17 | GSE4178 | GEO

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

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

Project description:Single cell transcriptomes of flow cytometry-sorted peripheral blood NK cells from COVID-19 patients and healthy controls. Single cell transcriptomes of peripheral blood NK cells from healthy donors stimulated with IL-12 and IL-15 +/- TGF-beta.

2021-10-25 | GSE184329 | GEO

Activin A and NK cell function

Project description:Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)- is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. We used a global, label-free proteomics approach to compare the protein expression profiles of NK cells in the presence of TGF-b or activin-A.

2020-04-06 | PXD011672 | Pride

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.

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