Engagement of TLR3, TLR7, and NKG2D Regulate IFN-γ Secretion but Not NKG2D-Mediated Cytotoxicity by Human NK Cells Stimulated with Suboptimal Doses of IL-12

Girart, Marı́a Victoria; Fuertes, Mercedes; Domaica, Carolina Inés; Rossi, Liliana; Zwirner, Norberto Walter

doi:10.4049/jimmunol.179.6.3472

Cited by 107 publications

(110 citation statements)

References 49 publications

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“…However, Raet1 overexpression and NKG2D ligation were not sufficient for priming the response to cytokine stimulation. TLR3, TLR7, and TLR9 are expressed in NK cells and are functionally dependent on the presence of accessory cytokines (53,54). In agreement with our in vivo data, in vitro costimulation of human NK cells with viral PAMPs and NKG2D ligands, in the presence of accessory cytokines, led to more IFN-g production than either stimulation alone (53).…”

Section: Discussionsupporting

confidence: 80%

“…TLR3, TLR7, and TLR9 are expressed in NK cells and are functionally dependent on the presence of accessory cytokines (53,54). In agreement with our in vivo data, in vitro costimulation of human NK cells with viral PAMPs and NKG2D ligands, in the presence of accessory cytokines, led to more IFN-g production than either stimulation alone (53). Therefore, we propose that prior NKG2D stimulation on NK cells primes cell-autonomous TLR signaling, and CS exposure-driven NKG2D activation of NK cells likely synergizes with the additional priming mechanisms described above.…”

Section: Discussionmentioning

confidence: 99%

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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: 80%

Section: Discussionmentioning

confidence: 99%

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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“…type I IFN, IL-2, or IL-12) [16], or directly by some TLR agonists. As an example, the TLR3 agonist polyI:C, which mimics double-strand viral RNA [17], acts synergistically with IL-2 and IL-12 to induce IFN-g production by human NK cells [18][19][20]. Murine NK cells also express functional TLR and produce IFN-g in response to TLR3 agonist [21,22].…”

Section: Introductionmentioning

confidence: 99%

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

et al. 2009

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NK lymphocytes and type I IFN (IFN-a/b) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-b (but not IFN-a) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-b Ab prevented the production of IFN-c induced by polyI:C plus IL-2/IL-12. Similarly, IFN-c production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1 À/À compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-c production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-b that induce, in an autocrine manner, the production of IFN-c and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.Key words: IFN-g . NK cells . PolyI:C . Type I IFN IntroductionType I IFN is a multi-member cytokine family, in which IFN-a and -b are the main types of interest from an immunological perspective [1,2]. They are involved in anti-viral immunity and in some immune disorders (such as autoimmune diseases). In addition to directly interfering with viral replication, type I IFN have anti-proliferative and immunoregulatory properties. They bridge innate and adaptive immune responses by inducing DC maturation and favoring antigen cross-presentation [3]. They also act directly on CD8 1 T cells to favor the generation of effector and memory T cells [4]. The expression of type I IFN is induced early upon recognition of viruses or viral moieties by some innate receptors of the TLR or RIG-1-like receptor families [5]. IFN-a is mainly secreted by plasmacytoid DC in response to viral nucleic acids recognized by TLR7 and 9 [6]. IFN-b mRNA expression is induced in numerous cell types by TLR stimulation [7,8]. IFN-b has a short half-time, is difficult to quantify, and its secretion is mainly evidenced indirectly by neutralizing its activity in in vitro assay [9]. Owing to the central role of type I IFN in the [11]. These cells kill virally infected cells and tumoral cells in the absence of prior activation [11,12]. NK-cell cytotoxic activity is tightly regulated by inhibitory and activatory receptors [13]. Consequently, NK cells are important during the early phases of viral infection, while antigen-specific T-and B-cell responses are generated. In addition to cytotoxic properties, NK cells have immunoregulatory functions. Through the expression of cell surface molecules and the secretion of cytokines such as IFN-g, they directly modulate macrophages, B and T lymphocyte and DC functions [11,12,14,15]. Consequently, in addition to a protective role in anti-tumor and antiviral immunity, it is now suggested that NK c...

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“…The recognition of target cells is mediated by a complex repertoire of activating and inhibitory receptors allowing for the discrimination between normal and infected/transformed cells. An extra level of regulation of NK cell activation is provided by diverse cytokines (3,4) and the recognition of pathogen-associated molecular patterns through TLRs (5). NK cell activation results not only in a cytotoxic response toward target cells, but also in the secretion of IFN-g and other cytokines and chemokines (6)(7)(8), rendering NK cells capable of modulating the activity of other cells of the immune system and the outcome of the immune response (9)(10)(11).…”

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confidence: 99%

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

Iraolagoitia

Spallanzani

Torres

et al. 2016

The Journal of Immunology

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Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8+ T cells, leading to reduced memory responses. After challenge with MC57 cells transduced to express the model Ag SIY (MC57.SIY), NK cell–depleted mice exhibited a significantly higher frequency of SIY-specific CD8+ T cells, with enhanced IFN-γ production and cytotoxic capability. Depletion of NK cells resulted in a CD8+ T cell population skewed toward an effector memory T phenotype that was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Dendritic cells (DCs) from NK cell–depleted tumor-bearing mice exhibited a more mature phenotype. Interestingly, tumor-infiltrating and tumor-draining lymph node NK cells displayed an upregulated expression of the inhibitory molecule programmed death ligand 1 that, through interaction with programmed death-1 expressed on DCs, limited DC activation, explaining their reduced ability to induce tumor-specific CD8+ T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on antitumor immunity, a finding with implications for immunotherapy in the clinic.

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Engagement of TLR3, TLR7, and NKG2D Regulate IFN-γ Secretion but Not NKG2D-Mediated Cytotoxicity by Human NK Cells Stimulated with Suboptimal Doses of IL-12

Cited by 107 publications

References 49 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

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

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