Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection

Helden, Mary J. van; Goossens, Steven; Daussy, Christophe; Mathieu, Alban; Faure, Fabrice; Marçais, Antoine; Vandamme, Niels; Farla, Natalie; Mayol, Katia; Viel, Sébastien; Degouve, Sophie; Debien, Emilie; Seuntjens, Eve; Conidi, Andrea; Chaix, Julie; Mangeot, Philippe; Bernard, Simon; Buffat, Laurent; Haigh, Jody J.; Huylebroeck, Danny; Lambrecht, Bart N.; Berx, Geert; Walzer, Thierry

doi:10.1084/jem.20150809

Cited by 141 publications

(120 citation statements)

References 25 publications

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“…The overwhelming number of metastatic nodules present in Smad4 f/f Ncr1 iCre mice mirrored the results of studies in which NK cells are absent in the lung 27 . Analysis of the frequency and number of NK cells revealed that these cells were present in the lungs of all mice at day 15 of B16 tumor metastatic model, although fewer were present in Smad4 f/f Ncr1 iCre mice than in their Smad4 f/f littermates (Fig.…”

Section: Resultssupporting

confidence: 68%

SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling

et al. 2017

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Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of ‘imprinting’ by cytokines of the TGF-β family. We examined mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGF-βR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells.

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Section: Resultssupporting

confidence: 68%

SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling

et al. 2017

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“…T-BET is a key transcription factor for antigen-driven effector function in CD8 + T cells (25) and terminal maturation, homeostasis and IFNG transcription in NK and Vα14 i NKT cells (26). T-BET induces the expression of two other transcription factors, zinc finger E-box-binding protein (ZEB) 2 and PR domain-containing protein (PRDM) 1 (BLIMP-1) that promote NK cell maturation, homeostasis and function (27, 28). To determine whether GSK3 inhibition increases TBX21 transcription in NK cells, CD3/19-depleted cells were cultured for 7 days with 10 ng/ml IL-15 and either DMSO or CHIR99021.…”

Section: Resultsmentioning

confidence: 99%

“…Both T-BET and its homolog EOMES control NK cell transit through maturational checkpoints and promote NK cell cytotoxicity and IFN-γ production (31). T-BET controls late-stage NK cell maturation by increasing transcription of ZEB2, which is essential for the survival of mature NK cells, and BLIMP-1, which is required for NK cell maturation and homeostasis (27, 28). Our results are consistent with a recent study by Taylor et al, who demonstrated increased Tbx21 expression in mouse CD8 + T cells cultured ex vivo with GSK3 inhibitors or with siRNA knockdown of GSK3.…”

Section: Discussionmentioning

confidence: 99%

GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity

et al. 2017

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Maturation of human natural killer cells (NK cells) as defined by accumulation of cell surface expression of CD57 is associated with increased cytotoxic character and TNF and IFN-γ production upon target cell recognition. Notably, multiple studies point to a unique role for CD57+ NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacological inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL-15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK cell maturation including T-BET, ZEB2 and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded ex vivo in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFN-γ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity (ADCC). In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy.

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“…While ZEB2 was shown to be downstream of T-bet, and these two factors co-regulate many of the same genes, it appears that ZEB2 modulates these downstream genes independently. Given that ZEB2 plays a similar role in the maturation Natural Killer cells [50], and is required for the development of plasmacytoid dendritic cells and monocytes [33], it would be relevant to assess whether ZEB2 has similar functions in the differentiation of CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154

Kunnath-Velayudhan

Goldberg

Saini

et al. 2017

The Journal of Immunology

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Analysis of antigen-specific CD4+ T cells in mycobacterial infections at the transcriptome level is informative but technically challenging. While several methods exist for identifying antigen-specific T cells, including intracellular cytokine staining, cell surface cytokine-capture assays, and staining with peptide:MHC-II multimers, all of these have significant technical constraints that limit their usefulness. Measurement of activation-induced expression of CD154 has been reported to detect live, antigen-specific CD4+ T cells but this approach remains underexplored, and to our knowledge has not previously been applied in mycobacteria-infected animals. Here we show that CD154 expression identifies adoptively transferred or endogenous antigen-specific CD4+ T cells induced by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccination. We confirmed that antigen-specific cytokine production was positively correlated with CD154 expression by CD4+ T cells from BCG-vaccinated mice, and show that high quality microarrays can be performed from RNA isolated from CD154+ cells purified by cell sorting. Analysis of microarray data demonstrated that the transcriptome of the CD4+ CD154+ cells was distinct from that of CD154− cells, and showed major enrichment of transcripts encoding multiple cytokines and pathways of cellular activation. One notable finding was the identification of a previously unrecognized subset of mycobacteria-specific CD4+ T cells characterized by the production of interleukin-3. Our results support the use of CD154 expression as a practical and reliable method to isolate live, antigen-specific CD4+ T cells for transcriptomic analysis and potentially for a range of other studies in infected or previously immunized hosts.

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Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection

Abstract: The transcription factor Zeb2 cooperates with T-bet to control NK cell maturation, viability, and exit from the bone marrow and is essential for rejection of melanoma lung metastasis.

Cited by 141 publications

References 25 publications

SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling

SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling

GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity

Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154

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