Activation of NK cell cytotoxicity

Smyth, Mark J.; Cretney, Erika; Kelly, Janice M.; Westwood, Jennifer A.; Street, Shayna E.A.; Yagita, Hideo; Takeda, Kazuyoshi; Dommelen, Serani L.H. van; Degli-Esposti, Mariapia A.; Hayakawa, Yoshihiro

doi:10.1016/j.molimm.2004.07.034

Cited by 588 publications

(463 citation statements)

References 93 publications

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“…NK cells are mediators of immunity against various infectious diseases and tumor cells, performing direct cell-mediated cytotoxicity and producing cytokines in response to cell-associated and soluble stimuli [6,7]. They additionally shape adaptive immune responses, mainly through the production of cytokines [8].…”

Section: Introductionmentioning

confidence: 99%

Germ‐line and rearranged Tcrd transcription distinguish bona fide NK cells and NK‐like γδ T cells

et al. 2007

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NK cells and cd T cells are distinct subsets of lymphocytes that contextually share multiple phenotypic and functional characteristics. However, the acquisition and the extent of these similarities remain poorly understood. Here, using T cell receptor d locus-histone 2B-enhanced GFP (Tcrd-H2BEGFP) reporter mice, we show that germline transcription of Tcrd occurs in all maturing NK cells. We also describe a population of mouse NK-like cells that are indistinguishable from "bona fide" NK cells using standard protocols. Requirements for V(D)J recombination and a functional thymus, along with very low-level expression of surface TCRcd but high intracellular CD3, define these cells as cd T cells. "NK-like cd T cells" are CD127 + , have a memory-activated phenotype, express multiple NK cell receptors and readily produce interferon-c in response to IL-12/IL-18 stimulation. The close phenotypic resemblance between NK cells and NK-like cd T cells is a source of experimental ambiguity in studies bridging NK and T cell biology, such as those on thymic NK cell development. Instead, it ascribes chronic TCRcd engagement as a means of acquiring NK-like function. IntroductionClassification of NK cells and some cd T cell subsets as innate immune cells is argued by their recognition and response to self ligands and microbial molecules without any requirement for prior specific immunization [1][2][3][4][5]. NK cells are mediators of immunity against various infectious diseases and tumor cells, performing direct cell-mediated cytotoxicity and producing cytokines in response to cell-associated and soluble stimuli [6,7]. They additionally shape adaptive immune responses, mainly through the production of cytokines [8]. Their activation is regulated through germ-line-encoded receptors including NKG2D, the natural cytotoxicity receptors and inhibitory receptors for MHC class I, many of which recognize self-encoded ligands [9][10][11]. Most cd T cell subsets are unconventional T cells that -similar to CD1d-restricted Va14i NKT cells, MR1-restricted MAIT cells and certain populations of CD8 + T cells -are not restricted to classical MHC class I-or MHC class II-bearing specific peptides [2,3]. They have heterogeneous effector functions associated with differential TCRcd usage. Roles have been described in immunity against infectious pathogens and tumors [12] and cd T cells have been strongly implicated in immunosuppressive regulation of the immune system and in the process of wound healing [13,14]. Using TCR transfer experiments, or direct ligand binding, TCRcd ligands have been described for a small number of subsets [5]. In the mouse, cd T cell subsets recognize the non-classical MHC class I molecules T10/T22 [15], and an unknown ligand expressed by keratinocytes [16]. In humans, some Vd1 cd T cells recognize non-classical MHC class I molecules MICA and MICB, and Vc9Vd2 cd T cells have been reported to recognize self and bacterial phosphoantigens, and a complex formed between F1-ATP synthase and apolipoprotein A-1 [5,[17][18][19][20].Du...

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Section: Introductionmentioning

confidence: 99%

Germ‐line and rearranged Tcrd transcription distinguish bona fide NK cells and NK‐like γδ T cells

et al. 2007

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“…The effectors of this arm of the innate response are NK cells 63 , and the TAM signalling system also has an important role in regulating the activity of these cells 22 . This regulation again appears to be carried out in concert with cytokine receptors.On activation, NK cells kill their target cells through the exocytosis of perforin-and granzyme-containing granules, and the secretion of CD95 ligand and TNF-related apoptosisinducing ligand (TRAIL) [64][65][66][67][68] . NK cells also produce a variety of cytokines, including IFNγ, TNF and granulocyte/macrophage colony-stimulating factor (GM-CSF) [69][70][71] .…”

mentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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“…27,31,35 Additionally, we examined the death receptors TRAIL-R2 (DR5) and Fas, both known to be involved in NK-mediated tumor lysis. 46,47 The carcinoma types we examined were also expanded to include not only prostate (DU145 and PC-3) and non-small cell lung (H441 and H460), but also small-cell lung (H1882), triple-negative breast (MDA-MB-231 and SUM159PT), and ovarian (HEY-T30) cancers. The effect of entinostat was assessed by exposing these carcinoma cells in vitro to DMSO or entinostat as described before analyzing by flow cytometry the surface expression of the aforementioned proteins.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

et al. 2018

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Checkpoint inhibitors targeting the PD-1/PD-L1 axis are promising immunotherapies shown to elicit objective responses against multiple tumor types, yet these agents fail to benefit most patients with carcinomas. This highlights the need to develop effective therapeutic strategies to increase responses to PD-1/PD-L1 blockade. Histone deacetylase (HDAC) inhibitors in combination with immunotherapies have provided preliminary evidence of anti-tumor effects. We investigated here whether exposure of either natural killer (NK) cells and/or tumor cells to two different classes of HDAC inhibitors would augment (a) NK cell‒mediated direct tumor cell killing and/or (b) antibody-dependent cellular cytotoxicity (ADCC) using avelumab, a fully human IgG1 monoclonal antibody targeting PD-L1. Treatment of a diverse array of human carcinoma cells with a clinically relevant dose of either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat significantly enhanced the expression of multiple NK ligands and death receptors resulting in enhanced NK cell‒mediated lysis. Moreover, HDAC inhibition enhanced tumor cell PD-L1 expression both in vitro and in carcinoma xenografts. These data demonstrate that treatment of a diverse array of carcinoma cells with two different classes of HDAC inhibitors results in enhanced NK cell tumor cell lysis and avelumab-mediated ADCC. Furthermore, entinostat treatment of NK cells from healthy donors and PBMCs from cancer patients induced an activated NK cell phenotype, and heightened direct and ADCC-mediated healthy donor NK lysis of multiple carcinoma types. This study thus extends the mechanism and provides a rationale for combining HDAC inhibitors with PD-1/PD-L1 checkpoint blockade to increase patient responses to anti-PD-1/PD-L1 therapies.

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Activation of NK cell cytotoxicity

Cited by 588 publications

References 93 publications

Germ‐line and rearranged Tcrd transcription distinguish bona fide NK cells and NK‐like γδ T cells

Germ‐line and rearranged Tcrd transcription distinguish bona fide NK cells and NK‐like γδ T cells

Immunobiology of the TAM receptors

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

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