NKG2D receptor activation of NF-κB enhances inflammatory cytokine production in murine effector CD8+ T cells

Whitman, Emily; Barber, Amorette

doi:10.1016/j.molimm.2014.07.015

Cited by 22 publications

(24 citation statements)

References 50 publications

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“…40 In contrast, silencing NKG2D and DAP10 can reduce the cytotoxcity of T and NK cell, 41 and NKG2D dysfunction impairs anti-tumor activities of memory CD8 + T cell. 42 Besides, activation of NKG2D and DAP10 also enhance the inflammatory cytokine production by murine CD8 + T cells as reported previousl, 43,44 and NKG2D signaling are also able to promote T cell infiltration and accumulation in tumors and live, 45,46 which are consistent with our in vivo results obtained from lung cancer PDX mouse model.…”

Section: Discussionsupporting

confidence: 92%

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

et al. 2018

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Chimeric antigen receptor (CAR) T cell immunotherapies have shown remarkable efficacy in treating multiple types of hematological malignancies but are not sufficiently effective at treating solid tumors. NKG2D is a strong activating receptor for NK cells and a co-stimulatory receptor for T cells. NKG2D signal transduction depends on DNAX-activating protein 10 (DAP10). Here, we introduced the cytoplasmic domain of DAP10 into the second-generation CARs M28z and G28z to generate M28z10 and G28z10, which target mesothelin (MSLN) and glypican 3 (GPC3), respectively. T cells expressing M28z10 or G28z10 showed enhanced and prolonged effector function against MSLN+ lung cancer or GPC3+ hepatocellular carcinoma cell lines in culture and secreted elevated levels of cytokines, including IL-2, IFN-γ, granzyme B, and GM-CSF. In addition, M28z10 CAR-T cells showed greater anti-tumor activity than those expressing M28z in both A549 cell line xenografts and human lung cancer patient-derived xenografts (PDX). Similarly, G28z10 exhibited higher efficacy in causing tumor regression than did G28z in hepatocellular carcinoma PDX. Therefore, our results show that DAP10 signaling contributes to the function of CAR-T cells in both lung cancer and hepatocellular carcinoma and can enhance the efficacy of CAR-T cells.

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Section: Discussionsupporting

confidence: 92%

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

et al. 2018

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“…The levels of IL-6 and IL-12 F I G U R E 2 Effects of silkworm pupa oil on hepatic histology (original magnification 100×). NF-κB subunits p50/p65 are bound to the inhibitory protein IκBα and exist in cytosol as an inactive form (Evans, Rodino, Adcox, & Carlyon, 2018;Whitman & Barber, 2015). n = 6 are increased in primary human hepatocytes and mice with APAP treatment (Cho et al, 2015;Kim et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the activation of NF-κB signaling can induce the production of proinflammatory cytokines and hepatic inflammation. NF-κB subunits p50/p65 are bound to the inhibitory protein IκBα and exist in cytosol as an inactive form (Evans, Rodino, Adcox, & Carlyon, 2018;Whitman & Barber, 2015).…”

Section: Discussionmentioning

confidence: 99%

Silkworm pupa oil attenuates acetaminophen‐induced acute liver injury by inhibiting oxidative stress‐mediated NF‐κB signaling

Long

Song

Zhao

et al. 2019

Food Science & Nutrition

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Acetaminophen (APAP) overdose causes severe hepatotoxicity and acute liver failure. The current study aims to investigate the protection effects of silkworm pupa oil (SPO) against acute hepatic injury in APAP‐exposed Kunming mice. Our results showed that the liver index and the levels of serum alanine transaminase (ALT) and aspartate transaminase (AST) in mice subjected to APAP treatment were decreased by SPO. Supplement of SPO also restored hepatic histopathological alterations induced by APAP. The APAP‐induced increase in proinflammatory cytokines, including TNF‐α, IL‐6, and IL‐12, was reversed by SPO, which was mediated by the reduction of nuclear factor (NF)‐κB p65 expression and the increase in the expression of IκB‐α in liver tissue. Moreover, SPO inhibited APAP‐triggered oxidative stress by decreasing MDA level and increasing the activities of SOD and GSH‐Px. Collectively, SPO attenuated hepatic injury induced by APAP, which attributed to the suppression of oxidative stress‐mediated NF‐κB signaling. Our findings suggest that SPO supplementation may be potential strategy against acute hepatic injury.

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“…NKG2D ligand expression on cells can activate NKG2D + lymphocytes, resulting in increased killing of the ligand-expressing cells and/or production of cytokines, such as IFN-γ, TNF-α, and GM-CSF (Boukouaci et al, 2013; Poggi and Zocchi, 2006; Whitman and Barber, 2015). In agreement with this, we observed a positive correlation between the frequency of NKG2D ligand-expressing cells and the release of pro-inflammatory cytokines from CD biopsies in an ex vivo assay.…”

Section: Discussionmentioning

confidence: 99%

NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration

Vadstrup

Galsgaard

Jensen

et al. 2017

Experimental and Molecular Pathology

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Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1–6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn’s disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4–6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.

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NKG2D receptor activation of NF-κB enhances inflammatory cytokine production in murine effector CD8+ T cells

Cited by 22 publications

References 50 publications

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

Silkworm pupa oil attenuates acetaminophen‐induced acute liver injury by inhibiting oxidative stress‐mediated NF‐κB signaling

NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration

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