Cutting Edge: Priming of NK Cells by IL-18

Chaix, Julie; Tessmer, Marlowe S.; Hoebe, Kasper; Fuséri, Nicolas; Ryffel, Bernhard; Dalod, Marc; Alexopoulou, Lena; Beutler, Bruce; Brossay, Laurent; Vivier, Éric; Walzer, Thierry

doi:10.4049/jimmunol.181.3.1627

Cited by 281 publications

(244 citation statements)

References 25 publications

(30 reference statements)

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“…Primed NK cells then exit the LNs and enter circulation where they execute effector functions upon secondary stimulation, presumably by infected cells (19). NK cell priming requires type I IFNs and IL-15, but IL-18 can also prime NK cells (19,47). IL-12 is dispensable for NK cell priming, but in agreement with our data, IL-12 enhances production of IFN-g from primed NK cells (19).…”

Section: Discussionsupporting

confidence: 79%

Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

Motz¹,

Eppert²,

Wortham³

et al. 2010

The Journal of Immunology

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Chronic obstructive pulmonary disease (COPD) is a debilitating, progressive lung disease punctuated by exacerbations of symptoms. COPD exacerbations are most often associated with viral infections, and exposure to cigarette smoke (CS) followed by viral infection has been shown experimentally to enhance lung inflammation, tissue destruction, and airway fibrosis. Despite this, however, the cellular mechanisms responsible for this effect are unknown. In this study, we examined NK cell function in a mouse model of COPD given the vital role of NK cells following viral infection. Ex vivo stimulation of lung leukocytes with poly(I:C), ssRNA40, or ODN1826 enhanced production of NK cell-derived IFN-γ in CS-exposed mice. NK cells from CS-exposed mice exhibited a novel form of priming; highly purified NK cells from CS-exposed mice, relative to NK cells from filtered air-exposed mice, produced more IFN-γ following stimulation with IL-12, IL-18, or both. Further, NK cell priming was lost following smoking cessation. NKG2D stimulation through overexpression of Raet1 on the lung epithelium primed NK cell responsiveness to poly(I:C), ssRNA40, or ODN1826 stimulation, but not cytokine stimulation. In addition, NK cells from CS-exposed mice expressed more cell surface CD107a upon stimulation, demonstrating that the NK cell degranulation response was also primed. Together, these results reveal a novel mechanism of activation of the innate immune system and highlight NK cells as important cellular targets in controlling COPD exacerbations.

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Section: Discussionsupporting

confidence: 79%

Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

Motz¹,

Eppert²,

Wortham³

et al. 2010

The Journal of Immunology

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“…12 Here, arming refers to an enhanced NK-cell functional capacity in general, as opposed to a specific theory of NK-cell education. 11 The arming of murine NK cells for potent cytotoxicity can be induced in vitro by cytokines (eg, interleukin-2 [IL-2] or IL-15), or by activated accessory cells that stimulate NK cells in response to acute infection, [12][13][14] but the mechanisms whereby these arming events occur in the healthy host are unclear. In contrast to mice, most NK cells from the peripheral blood (CD56 dim ) of healthy humans are armed with preformed perforin and Gzm proteins within cytotoxic granules and mediate killing directly ex vivo.…”

Section: Introductionmentioning

confidence: 99%

Latent herpesvirus infection arms NK cells

White

Keppel²,

Schneider³

et al. 2010

Blood

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“…IL-15 is known to increase NK cell cytotoxic ability by inducing the production of granzyme B (38). IL-18 is a proinflammatory cytokine that is important for IFN-g production and can act in synergy with IL-15 to enhance NK cell activation (39)(40)(41). We assessed the production of IL-18 in IFN-a moDCs that were stimulated overnight with IL-32a, IL-15, or a combination of IL-15 and IL-32a.…”

Section: Il-32a Regulates Il-18 Production In Dcsmentioning

confidence: 99%

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

Gorvel

Korenfeld

Tung

et al. 2017

The Journal of Immunology

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Cytokines produced by dendritic cells (DCs) can largely determine the direction of immunity. Transcriptional analysis revealed that besides IL-15, IL-32 was the only other cytokine expressed by human Langerhans cells. IL-32 is a human cytokine that exists in four main isoforms. Currently, little is known about the regulation and function of the various IL-32 isoforms. In this study, we found that IL-15 is a potent inducer of IL-32α in DCs. Because IL-15 promotes NK cell activation, we investigated the interplay between IL-32 and IL-15 and their role in NK cell activity. We show that IL-32α acts on NK cells to inhibit IL-15–mediated STAT5 phosphorylation and to suppress their IL-15–induced effector molecule expression and cytolytic capacity. IL-32α also acted on DCs by downregulating IL-15–induced IL-18 production, an important cytokine in NK cell activity. Blocking IL-32α during DC:NK cell coculture enhanced NK cell effector molecule expression as well as their cytolytic capacity. Taken together, our findings suggest a feedback inhibition of IL-15–mediated NK cell activity by IL-32α.

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Cutting Edge: Priming of NK Cells by IL-18

Cited by 281 publications

References 25 publications

Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

Latent herpesvirus infection arms NK cells

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

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