Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation

Zhu, Shuchai; Phatarpekar, Prasad V.; Denman, Cecele J.; Senyukov, Vladimir; Somanchi, Srinivas S.; Nguyen-Jackson, Hoainam; Mace, Emily M.; Freeman, Alexandra F.; Watowich, Stephanie S.; Orange, Jordan S.; Holland, Steven M.; Lee, Dean A.

doi:10.1182/blood-2013-05-499707

Cited by 66 publications

(71 citation statements)

References 45 publications

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“…The surface levels of NKG2D on M1-primed NK cells also decreased after the masking of IL-23p19 (Fig. 3B), which is known to share with IL-12 some functional properties (46,47).…”

Section: M1 Macrophages Induce Nkp44 and Nkg2d Upregulation Via Il-1bmentioning

confidence: 89%

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways

Mattiola

Pesant

Tentorio

et al. 2015

The Journal of Immunology

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The cross talk between NK cells and macrophages is emerging as a major line of defense against microbial infections and tumors. This study reveals a complex network of soluble mediators and cell-to-cell interactions allowing human classically activated (M1) macrophages, but not resting (M0) or alternatively activated (M2) macrophages, to prime resting autologous NK cells. In this article, we show that M1 increase NK cell cytotoxicity by IL-23 and IFN-β-dependent upregulation of NKG2D, IL-1β-dependent upregulation of NKp44, and trans-presentation of IL-15. Moreover, both IFN-β-dependent cis-presentation of IL-15 on NK cells and engagement of the 2B4-CD48 pathway are used by M1 to trigger NK cell production of IFN-γ. The disclosure of these synergic cellular mechanisms regulating the M1-NK cell cross talk provides novel insights to better understand the role of innate immune responses in the physiopathology of tumor biology and microbial infections

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“…The surface levels of NKG2D on M1-primed NK cells also decreased after the masking of IL-23p19 (Fig. 3B), which is known to share with IL-12 some functional properties (46,47).…”

Section: M1 Macrophages Induce Nkp44 and Nkg2d Upregulation Via Il-1bmentioning

confidence: 89%

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways

Mattiola

Pesant

Tentorio

et al. 2015

The Journal of Immunology

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“…Zhu et al claimed that IL-21 initiated activation of STAT3, which accounts for the transcriptional induction of NKG2D expression on NK cells. 15 Inspired by this finding, we attempted to determine whether pSTAT3 is the downstream transcriptional factor for TCR and CD28 activation to induce NKG2D expression on CD8 C T cells. Given that a previous study reported that inhibition of the kinase activity of Lck Figure 8.…”

Section: Discussionmentioning

confidence: 99%

“…Zhu et al 15 found that IL-21 upregulated NKG2D expression on NK cells via phosphorylation of STAT3. In addition, STAT3 signaling is required for regulation of terminal differentiation of IgG B cells, 16 maintenance of Th17 cells, 17 and development of memory T cells.…”

Section: Introductionmentioning

confidence: 99%

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Batth

Xia

et al. 2016

OncoImmunology

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The natural killer (NK) group 2D (NKG2D) receptor, which displays on mouse and human NK cells, activates CD8 C T cells and small subsets of other T cells. NKG2D C CD8 C T cells play critical roles in both innate and adaptive immunity upon engagement with NKG2D ligands to eliminate tumor and infected cells. Despite the important role of NKG2D C CD8 C T cells in immune surveillance, the mechanisms of how NKG2D expression on CD8 C T cells is regulated remain poorly defined. We treated mouse and human CD8 C T cells with CD80 recombinant protein, plus a pharmacologic model with small molecular inhibitors to determine which signaling pathway leads to NKG2D regulation on CD8 C T cells. This study revealed that CD28 activation gives rise to sustained NKG2D expression on both mouse and human CD8 C T cells in a signal transducer and activator of transcription 3 (STAT3) phosphorylation-dependent manner. Further, we found that CD28 activation stimulated sustained activation of the tyrosine kinase Lck, which recruits and triggers Janus kinase/STAT3 signaling to phosphorylate STAT3, and in turn increases NKG2D expression. Moreover, NKG2D induction on CD8 C T cells exerts cytolytic activity against target tumor cells in vitro, as well as significantly improves the antitumor therapeutic effects in vivo in an NKG2D-dependent manner. Taken together, these results elucidated a novel mechanism of NKG2D regulation by phosphorylated STAT3 (pSTAT3) on CD8 C T cells upon CD28 activation. This mechanism may shed light on the effectiveness of CD80-based, NKG2D-dependent antitumor immunotherapy.

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“…35,36 We found lower expression of the NK cell activating receptor NKGD2 in Tyk2 ¡/¡ NK cells. Expression of NKG2D in splenic NK cells from na€ ıve mice is regulated in a STAT3-dependent, STAT1-and IFNAR1-independent manner, 40,50 suggesting a link between TYK2 and STAT3 functions. However, TYK2 deficiency did not recapitulate the increased expression of DNAM-1, GZMB and PRF1 reported in STAT3-deficient NK cells, 51 arguing against a general impairment of STAT3 activity in the absence of TYK2.…”

Section: Discussionmentioning

confidence: 99%

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

et al. 2015

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Abbreviations: CCL3, chemokine (C-C motif) ligand 3; CFSE, carboxyfluorescein diacetate succinimidyl ester; GzmB, granzyme B; IFN, interferon; IFNAR, interferon a and b receptor; IL, interleukin; IL-12Rb1, interleukin-12 receptor subunit b-1; iNK, immature natural killer; JAK, xJanus kinase; MACS, magnetic-activated cell sorting; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; miR, microRNA; mNK, mature natural killer; NK, natural killer; NKP, natural killer precursor; Prf1, perforin; SEM, standard error of the mean; STAT, signal transducer and activator of transcription; T-ALL, T cell acute lymphoblastic leukemia; TYK2, tyrosine kinase 2; TYK2 K923E , kinase-inactive tyrosine kinase 2; WT, wild-typeTyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2 ¡/¡ ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2 ¡/¡ mice and mice expressing a kinase-inactive version of TYK2 (Tyk2 K923E ), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2 ¡/¡ and Tyk2 K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2 ¡/¡ NK cells (and to a lesser extent of Tyk2 K923E NK cells) is impaired. In contrast, the production of interferon g (IFNg) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2 K923E NK cells against a range of target cells in vitro is higher than that of Tyk2 ¡/¡ NK cells. Consistently, Tyk2 K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2's kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.

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Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation

Cited by 66 publications

References 45 publications

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

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Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation

Cited by 66 publications

References 45 publications

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

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Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism