Recruitment and Activation of Natural Killer Cells<i>In vitro</i>by a Human Dendritic Cell Vaccine

Gustafsson, Karin; Ingelsten, Madeleine; Bergqvist, Linda; Nyström, Jenny; Åndersson, Bengt; Karlsson‐Parra, Alex

doi:10.1158/0008-5472.can-07-6494

Cited by 74 publications

(100 citation statements)

References 48 publications

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“…DC maturation induced by IFN-g/FMKp led to an enhanced (41.5-fold increase in chemiluminescence) secretion of eleven chemokines as compared with TNF-a/PGE2-induced maturation. These chemokines included CCL5, CXCL10 and CCL19 to which NK cells can respond [23][24][25]. Quantification with ELISA confirmed that these chemokines were indeed produced by IFN-g/FMKp-matured DC and not by TNF-a/PGE2-matured DC (Fig.…”

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confidence: 74%

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

et al. 2010

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Besides their role in destruction of altered self-cells, NK cells have been shown to potentiate T-cell responses by interacting with DC. To take advantage of NK-DC crosstalk in therapeutic DC-based vaccination for infectious diseases and cancer, it is essential to understand the biology of this crosstalk. We aimed to elucidate the in vitro mechanisms responsible for NK-cell recruitment and activation by DC during infection. To mimic bacterial infection, DC were exposed to a membrane fraction of Klebsiella pneumoniae, which triggers TLR2/4. DC matured with these bacterial fragments can actively recruit NK cells in a CCR5-dependent manner. An additional mechanism of DC-induced NK-cell recruitment is characterized by the induction of CCR7 expression on CD56 dim CD16 1 NK cells after physical contact with membrane fraction of K. pneumoniae-matured DC, resulting in an enhanced migratory responsiveness to the lymph node-associated chemokine CCL19. Bacterial fragment-matured DC do not only mediate NK-cell migration but also meet the prerequisites needed for augmentation of NK-cell cytotoxicity and IFN-c production, the latter of which contributes to Th1 polarization.Key words: CCR5 . CCR7 . NK-DC interaction . Th1 polarization Supporting Information available online Introduction NK cells are important effector cells in the innate immune response against virally infected or malignantly transformed cells and their cytotoxicity is regulated by a delicate balance of inhibitory and activating signals [1]. Recent studies suggest that the interplay between NK cells and DC, the specialized antigenpresenting cell of the innate immune system [2], is critical in shaping the adaptive immune response [3]. This concept originates from several lines of evidence including: the discovery of NK cells colocalizing with DC in the T-cell areas of lymph nodes [4,5], the coupling of NK-cell recruitment to lymph nodes Ã These authors contributed equally to this work. 3138with the induction of more potent Th1 skewing [3], and the identification of NK-cell subpopulations with helper properties [6]. Although the exact mechanisms of NK-DC interaction remain to be elucidated, increasing evidence supports the importance of bidirectional NK-DC crosstalk [7,8].On the one hand, NK-DC crosstalk is characterized by the capacity of activated NK cells to induce DC maturation with elevated IL-12p70 production and subsequently an increased capacity to induce Th1 and CTL responses [9]. This NK-induced DC maturation depends at least in part on soluble factors such as and as well as on engagement of the natural cytotoxicity triggering receptor 30 [12]. Moreover, NK cells control the quality of the adaptive immune response by natural cytotoxicity triggering receptor 30-mediated lysis of immature or inadequately matured DC [13], enabling only fully mature DC to migrate into lymph nodes and subsequently prime T cells. On the other hand, DC are able to induce NK-cell proliferation, augmentation of cytotoxicity and cytokine secretion [8]. The DC-induced modulati...

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Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

et al. 2010

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“…They Correspondence: Dr. Sam K. P. Kung e-mail: Sam.Kung2@med.umanitoba.ca acquire specific chemokine surface receptors during development and maturation [2,[10][11][12][13][14][15]. Chemokine receptors such as CCR7, CCR5, and CXCR3 are involved in the preferential migrations and localization of NK cells into the LNs [8,[16][17][18][19], whereas NK cells reside in blood, liver, and spleen exhibit higher CXCR1 and CX 3 CR1 expression [8,9,[20][21][22][23][24][25]. Nonchemokine family proteins such as chemerin and SIP 5 are also involved in the regulation of NK-cell trafficking [26,27].…”

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Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

et al. 2014

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Migration and localization of NK cells into peripheral tissues are tightly regulated under normal and pathological conditions. The physiological importance of NK cell-DC crosstalk has been well documented. However, the ways in which DCs regulate the migratory properties of NK cells (such as chemotaxis, chemokinesis, chemo-repulsion) are not fully defined in vitro. Here, we employed a microfluidic platform to examine, at the single-cell level, C57BL/6 NK-cell migrations in a stable chemical gradient. We observed that soluble factors released by the immature and LPS-activated mature DCs induced a high level of chemotactic movement of IL-2-activated NK cells in vitro. We confirmed these findings in a standard trans-well migration assay, and identified CXCR3 as a key receptor on the NK cells that mediated the migration. More interestingly, we revealed a novel function of granulocyte macrophage colony-stimulating factor in repulsing NK-cell migrations. The future uses of such microfluidic device in the systematic evaluations of NK-cell migratory responses in NK cell-DC crosstalk will provide new insights into the development of DC-based NK-cell therapies against tumor and infections.Keywords: Bone marrow-derived dendritic cells r Chemo-repulsion r Chemotaxis r Microfluidic device r Natural killer cell r NK-DC crosstalk Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells are motile bone marrow (BM)-derived lymphocytes that play a key role in innate immunity against viral, microbial infections, and transformed cells [1][2][3]. They are capable of killing transformed or infected cells [1,2,4,5], and/or producing cytokines/chemokines that can profoundly influence the quality and magnitude of the adaptive immune responses [6][7][8][9]. They Correspondence: Dr. Sam K. P. Kung e-mail: Sam.Kung2@med.umanitoba.ca acquire specific chemokine surface receptors during development and maturation [2,[10][11][12][13][14][15]. Chemokine receptors such as CCR7, CCR5, and CXCR3 are involved in the preferential migrations and localization of NK cells into the LNs [8,[16][17][18][19], whereas NK cells reside in blood, liver, and spleen exhibit higher CXCR1 and CX 3 CR1 expression [8,9,[20][21][22][23][24][25]. Nonchemokine family proteins such as chemerin and SIP 5 are also involved in the regulation of NK-cell trafficking [26,27]. Collectively, they highlight the complexity of the environmental regulation of NK-cell migrations in physiological and pathological conditions. NK-cell activation and functions are regulated by cytokine/ chemokine and/or DC in the microenvironments [18,[28][29][30] [36,37]. In this report, we demonstrated an application of such microfluidic device in examining how soluble factors produced by DC regulated NK-cell migrations in vitro. Results A microfluidic platform to perform live-cell imaging of NK-cell migrationsWe used the established Y-shaped microfluidic device to examine chemotactic or chemo-repulsive movements of NK cells ...

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“…A line of evidence indicates that NK cells can regulate DC function and that NK-DC cross-regulation plays an important role in dictating the quality and the quantity of the adaptive immune responses (16)(17)(18)(19)(20)(21). A recent study showed that NK cells can enhance the capacity of DC to present parasitic Ags via the NKG2D receptor pathway (21).…”

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confidence: 99%

“…A recent study showed that NK cells can enhance the capacity of DC to present parasitic Ags via the NKG2D receptor pathway (21). The important role of DC in initiation and maintenance of T cell responses to chlamydial infection has been demonstrated by several previous studies using mouse models of C. trachomatis mouse pneumonitis strain, more recently called Chlamydia muridarum (22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

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NK Cells Promote Type 1 T Cell Immunity through Modulating the Function of Dendritic Cells during Intracellular Bacterial Infection

Jiao

Gao

Joyee

et al. 2011

The Journal of Immunology

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Dendritic cells (DC) play a key role in establishing protective adaptive immunity in intracellular bacterial infections, but the cells influencing DC function in vivo remain unclear. In this study, we investigated the role of NK cells in modulating the function of DC using a murine Chlamydia infection model. We found that the NK cell-depleted mice showed exacerbated disease after respiratory tract Chlamydia muridarum infection, which was correlated with altered T cell cytokine profile. Furthermore, DC from C. muridarum-infected NK-depleted mice (NK−DC) exhibited a less mature phenotype compared with that of DC from the infected mice without NK depletion (NK+DC). NK−DC produced significantly lower levels of both IL-12 and IL-10 than those of NK+DC. Moreover, NK−DC showed reduced ability to direct primary and established Ag-specific Th1 CD4+ T cell responses in DC–T coculture systems. More importantly, adoptive transfer of NK−DC, in contrast to NK+DC, failed to induce type 1 protective immunity in recipients after challenge infection. Finally, NK cells showed strong direct enhancing effect on IL-12 production by DC in an NK–DC coculture system, which was partially reduced by blocking NKG2D receptors signaling and virtually abolished by neutralizing IFN-γ activity. The data demonstrate a critical role of NK cells in modulating DC function in an intracellular bacterial infection.

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Recruitment and Activation of Natural Killer CellsIn vitroby a Human Dendritic Cell Vaccine

Abstract: Recruitment of circulating natural killer (NK) cells into inflamed lymph nodes is known to provide a potent, IFN-

Cited by 74 publications

References 48 publications

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

NK Cells Promote Type 1 T Cell Immunity through Modulating the Function of Dendritic Cells during Intracellular Bacterial Infection

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