Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster

Kim, Miju; Kim, Tae Jin; Kim, Hye Mi; Doh, Junsang; Lee, Kyung Mi

doi:10.1038/srep40623

Cited by 20 publications

(21 citation statements)

References 40 publications

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“…Similarly, NK cell activation by IL12/15/18 has been shown to induce CD25 expression, boosting IL2-dependent proliferation in vitro and in vivo in tumor-bearing mice (9,37). Hence, the induction of CD25 following AFM13 exposure may enable NK cells to compete for low amounts of IL2 with regulatory T cells, which strictly limit the availability of IL2 due to their constitutive CD25 expression, restraining NK cell expansion after adoptive cell transfer (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells

Pahl

Koch

Götz

et al. 2018

Cancer Immunology Research

101

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CD16A is a potent cytotoxicity receptor on human natural killer (NK) cells, which can be exploited by therapeutic bispecific antibodies. So far, the effects of CD16A-mediated activation on NK cell effector functions beyond classical antibody-dependent cytotoxicity have remained poorly elucidated. Here, we investigated NK cell responses after exposure to therapeutic antibodies such as the tetravalent bispecific antibody AFM13 (CD30/CD16A), designed for the treatment of Hodgkin lymphoma and other CD30 lymphomas. Our results reveal that CD16A engagement enhanced subsequent IL2- and IL15-driven NK cell proliferation and expansion. This effect involved the upregulation of CD25 (IL2Rα) and CD132 (γ) on NK cells, resulting in increased sensitivity to low-dose IL2 or to IL15. CD16A engagement initially induced NK cell cytotoxicity. The lower NK cell reactivity observed 1 day after CD16A engagement could be recovered by reculture in IL2 or IL15. After reculture in IL2 or IL15, these CD16A-experienced NK cells exerted more vigorous IFNγ production upon restimulation with tumor cells or cytokines. Importantly, after reculture, CD16A-experienced NK cells also exerted increased cytotoxicity toward different tumor targets, mainly through the activating NK cell receptor NKG2D. Our findings uncover a role for CD16A engagement in priming NK cell responses to restimulation by cytokines and tumor cells, indicative of a memory-like functionality. Our study suggests that combination of AFM13 with IL2 or IL15 may boost NK cell antitumor activity in patients by expanding tumor-reactive NK cells and enhancing NK cell reactivity, even upon repeated tumor encounters. .

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Section: Discussionmentioning

confidence: 99%

CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells

Pahl

Koch

Götz

et al. 2018

Cancer Immunology Research

101

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“…Histones in collaboration with other pro-inflammatory molecules form the first line of defense to eliminate pathogens by initiating immunothrombosis, a complex process where neutrophil histones contribute to generate an intravascular scaffold for containment, exposure and destruction of pathogens [12, 24]. This process, illustrating the relevance of multi-cellular clusters to enable cross-talk between immune cells to eliminate microbial pathogens [7, 8], appears analogous to the capacity of histones to create both NK/tumor and T-cell/tumor clusters to improve NK and T cell anti-MM activity. This additional immunoregulatory ability of NK cells should be considered in immunotherapy strategies, especially given the fact that NK cells constitute 1–6% of leukocytes in PB.…”

Section: Discussionmentioning

confidence: 99%

“…The relevance of this cross-talk between immune cells is observed after microbial infection, where dendritic cells (DCs) activate NK cells through IL15 secretion leading to T cell and monocyte activation [5][6][7]. The coordination of these immune responses requires the creation of cellular clusters to enable intercellular cross-talk between immune cells [7,8]. We previously reported the relevance of this cell-cell contact as a mechanism leading to a transmissible cytotoxicity from cord blood derived NK cell (CB-NK) to neighboring multiple myeloma (MM) cells, as CB-NK cytotoxicity is transferred to 'primary' MM cells (1°MM) after contact; and afterwards, it is passed from 1°MM to adjacent 'secondary' MM cells (2°MM) unexposed to CB-NK [9].…”

Section: Introductionmentioning

confidence: 99%

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor

Martín-Antonio¹,

Suñé²,

Najjar³

et al. 2019

j. immunotherapy cancer

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BackgroundNatural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined.MethodsTRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred.ResultsWe describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity.ConclusionThis study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies.

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“…Such ability is triggered principally in response to other exogenous cytokines that supports the proliferation and function of NK cells ( 47 ), but as occurs with the cytotoxic activity, recognition of membrane-bound ligands on target cells also regulates the production of different mediators by certain NK cell subsets in humans ( 48 ). Moreover, NK cells can produce IL-2 to promote their proper activation after clustering in multicellular groups and come into cell-to-cell homotypic interactions ( 49 ).…”

Section: Biology Of Nk Cellsmentioning

confidence: 99%

Memory of Natural Killer Cells: A New Chance against Mycobacterium tuberculosis?

et al. 2017

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Natural killer (NK) cells are lymphocytes of the innate immune system, which play an important role in the initial defense against a wide variety of pathogens, including viruses and intracellular bacteria. NK cells produce cytokines that enhance immune responses directed toward pathogens and also exert cytotoxic activity against infected cells, thereby eliminating the reservoir of infection. Their role in defense against Mycobacterium tuberculosis (Mtb) has been recently studied, and there is increasing evidence that highlight the importance of NK cell function during pulmonary tuberculosis (PTB), especially in the absence of optimal T-cell responses. Additionally, in the last years, it has been observed that NK cells mediate secondary responses against antigens to which they were previously exposed, an ability classically attributed to lymphocytes of the adaptive branch of immunity. This phenomenon, called “innate memory,” could have important implications in the efforts to develop therapies and vaccines to improve the initial phases of immune reactions against different microorganisms, especially those to which there is not yet available vaccines to prevent infection, as is the case for tuberculosis. Therefore, the possibility of inducing memory-like NK cells ready to act prior to contact with Mtb or during the earliest stages of infection becomes quite interesting. However, our understanding of the mechanisms of innate memory remains incomplete. Here, we review recent literature about the mechanisms involved in the formation and maintenance of NK cell memory and the role of these cells in the immune response during tuberculosis. Finally, we discuss if the current evidence is sufficient to substantiate that NK cells exert more rapid and robust secondary responses after consecutive encounters with Mtb.

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Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster

Cited by 20 publications

References 40 publications

CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells

CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor

Memory of Natural Killer Cells: A New Chance against Mycobacterium tuberculosis?

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