Involvement of CD56brightCD11c+ Cells in IL-18–Mediated Expansion of Human γδ T Cells

Tsuda, Junko; Li, Wen; Yamanishi, Hiromichi; Yamamoto, Hideyuki; Okuda, A; Kubo, Shuji; Ma, Zhifeng; Terada, Nobuyuki; Tanaka, Yoshimasa; Okamura, Haruki

doi:10.4049/jimmunol.1001919

Cited by 36 publications

(60 citation statements)

References 49 publications

(69 reference statements)

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“…Our observation that IL-18 can boost the expansion of highly purified gd T cells clearly indicates that these CD56 bright CD11c + NK cells are not essential accessory cells and that IL-18 can costimulate gd T cells directly. In our study, depletion of CD56 + cells improved zoledronate-induced gd T cell expansion, which appears to be in contrast with previous reports (33). The apparent discrepancy may be due to the fact that depletion of CD56 + cells certainly eliminates CD56 bright CD11c + NK cells, which would otherwise support gd T cell expansion (33); however, it also (10 4 cells/96-well plate) in response to treatment was documented on days 3 and 6 using an Olympus CK2 microscope equipped with a ProgRes CT3 digital camera and ProgRes CapturePro 2.5 Software (Jenoptik) (original magnification 3400).…”

Section: Discussioncontrasting

confidence: 56%

“…Another accessory cell type that has been implicated in zoledronateinduced gd T cell expansion, particularly in the IL-18-mediated amplification, is the subset of CD56 bright CD11c + NK cells (33). Our observation that IL-18 can boost the expansion of highly purified gd T cells clearly indicates that these CD56 bright CD11c + NK cells are not essential accessory cells and that IL-18 can costimulate gd T cells directly.…”

Section: Discussionmentioning

confidence: 53%

“…IL-18, which is a stress-related, caspase-1-processed cytokine (31), was implicated in zoledronateinduced NK cell and gd T cell activation (29) and was shown to costimulate zoledronate-induced, IL-2-driven gd T cell expansion (32). A population of CD56 bright CD11c + NK cells was postulated to mediate the stimulatory effect of IL-18 in zoledronate-induced gd T cell expansion (33). In addition, B7-CD28, as well as CD27-CD70, costimulatory signals were reported to control survival, proliferation, and cytokine production of gd T cells (34,35).…”

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confidence: 99%

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Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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The potent nitrogen-containing bisphosphonate zoledronate inhibits farnesyl pyrophosphate synthase, a key enzyme of the mevalonate pathway that is often hyperactive in malignant cells. Zoledronate activates human Vγ9Vδ2 T cells, which are immune sentinels of cell stress and tumors, through upstream accumulation of the cognate Ag isopentenyl pyrophosphate. IL-18 was shown to enhance zoledronate-induced γδ T cell activation. Although monocytes have been considered important accessory cells that provide the Ag isopentenyl pyrophosphate, CD56brightCD11c+ NK cells were postulated to mediate the costimulatory effects of IL-18. We report in this article that downstream depletion of geranylgeranyl pyrophosphate (GGPP), which is required for protein prenylation, caused cell stress in monocytes, followed by caspase-1–mediated maturation and release of IL-18, which, in turn, induced γδ T cell CCL2. Likewise, zoledronate caused a substantial delay in γδ T cell expansion, which could be skipped by GGPP supplementation. Moreover, repletion of GGPP, which prevented acute zoledronate toxicity, and supplementation with IL-18, which strongly upregulated IL-2Rα (CD25) and favored the central memory phenotype, were sufficient to enable zoledronate-induced expansion of highly purified γδ T cells, even when starting cell numbers were as low as 104 γδ T cells. Our study reveals essential components of γδ T cell activation and indicates that exogenous IL-18, which can directly costimulate γδ T cells, eliminates the need for any accessory cells. Our findings will facilitate the generation of robust γδ T cells from small blood or tissue samples for cancer immunotherapy and immune-monitoring purposes.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 53%

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confidence: 99%

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Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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“…Although the ability of type I IFN to regulate CD69 expression, IFN-g secretion, and the cytotoxic function of human gd T cells has been well described in the literature (27)(28)(29), data regarding the role of IL-18 in activating human gd T cell function are sparse. For instance, IL-18 is involved in the proliferation of gd T cells that is stimulated by nitrogen-containing bisphosphonates (30). However, the role of IL-18 in regulating the antiviral function of human gd T cells has not been documented; therefore, we focused on studying this in subsequent experiments.…”

Section: Resultsmentioning

confidence: 99%

Type I IFNs and IL-18 Regulate the Antiviral Response of Primary Human γδ T Cells against Dendritic Cells Infected with Dengue Virus

Tsai

Liong

Gunalan

et al. 2015

The Journal of Immunology

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Little is known about the cellular mechanisms of innate immunity against dengue virus (DV) infection. Specifically, the γδ T cell response to DV has not been characterized in detail. In this article, we demonstrate that markers of activation, proliferation, and degranulation are upregulated on γδ T cells in PBMC isolated from individuals with acute dengue fever. Primary γδ T cells responded rapidly in vitro to autologous DV-infected dendritic cells by secreting IFN-γ and upregulating CD107a. The anti-DV IFN-γ response is regulated by type I IFN and IL-18 in a TCR-independent manner, and IFN-γ secreting γδ T cells predominantly expressed IL-18Rα. Antagonizing the ATP-dependent P2X7 receptor pathway of inflammasome activation significantly inhibited the anti-DV IFN-γ response of γδ T cells. Overnight priming with IL-18 produced effector γδ T cells with significantly increased ability to lyse autologous DV-infected dendritic cells. Monocytes were identified as accessory cells that augmented the anti-DV IFN-γ response of γδ T cells. Lack of monocytes in culture is associated with lower IL-18 levels in culture supernatant and diminished production of IFN-γ by γδ T cells, whereas addition of exogenous IL-18 restored the IFN-γ response of γδ T cells in monocyte-depleted cocultures with DV-infected DC. Our results indicate that primary γδ T cells contribute to the immune response during DV infection by providing an early source of IFN-γ, as well as by killing DV-infected cells, and suggest that monocytes participate as accessory cells that sense DV infection and amplify the cellular immune response against this virus in an IL-18–dependent manner.

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“…þ CTLs, and gd T cells which express IL18 receptors a/b chains and receptors containing immunoreceptor tyrosine-based activation motif (ITAM), and produce IFNg (23)(24)(25)(26)(27). In humans, IL18 promotes the expansion of CD56 bright CD11c þ HLA-DR þ helper NK cells, which may be a human counterpart of mouse precursors of mature natural killer (pre-mNK) cells, previously referred to as IFN-producing killer dendritic cells (28,29).…”

Section: Introductionmentioning

confidence: 99%

Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18

Yoshiya

et al. 2016

Clinical Cancer Research

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Purpose: Recent clinical trials and animal models demonstrated that immune checkpoint blockade enhanced effector cell responses and tumor rejection; however, further development and improvement of cancer immunotherapy is necessary for more favorable objective responses. In this study, we examined the effect of IL18 on the antitumor effect of immune checkpoint inhibitors.Experimental Design: We examined the effect of IL18 on the peritoneal dissemination of CT-26 cells or tail vein injection metastasis of B16/F10 cells using antiprogrammed death-1 ligand-1 (aPD-L1) and/or anti-CTL-associated antigen-4 (aCTLA-4) mAbs.Result: Massive ascites developed after intraperitoneal inoculation of CT-26, resulting in animal death within 30 days. Treatment of mice with aPD-L1 and/or aCTLA-4 significantly prolonged their survival, and a combination of the antibodies and IL18 provided a much greater therapeutic benefit. The combination modality led to the accumulation of precursor of mature natural killer (pre-mNK) cells in the peritoneal cavity together with increased CD8 þ T and decreased CD4Depletion of the pre-mNK cells abrogated the therapeutic effects and increased the number ofThe combination treatment also suppressed tail vein injection metastasis of B16/F10 cells. Conclusions:The results demonstrated that IL18 enhanced therapeutic effects of immune checkpoint blockade against peritoneal dissemination of carcinoma or tail vein injection metastasis of melanoma through accumulation of pre-mNK cells, memorytype CD8 þ T cells, and suppression of CD4

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Involvement of CD56brightCD11c+ Cells in IL-18–Mediated Expansion of Human γδ T Cells

Cited by 36 publications

References 49 publications

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Type I IFNs and IL-18 Regulate the Antiviral Response of Primary Human γδ T Cells against Dendritic Cells Infected with Dengue Virus

Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18

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