TNF-<i>α</i>Promotes IFN-<i>γ</i>-Induced CD40 Expression and Antigen Process in Myb-Transformed Hematological Cells

Gu, Wenyi; Chen, Jiezhong; Yang, Lei; Zhao, Kong‐Nan

doi:10.1100/2012/621969

Cited by 10 publications

(8 citation statements)

References 46 publications

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“…Tnfrsf1a and Tnfrsf1b were the 6 th and 50 th lowest β scores in the CD40 screen, respectively. Previous studies suggested that TNF stimulation enhances IFNγ-mediated CD40 expression in hematopoietic progenitors (80), and we confirmed this observation in macrophages (Figure 1E). We observed a 6-fold higher induction of CD40 in macrophages stimulated with a combination of IFNγ and TNF compared to IFNγ alone.…”

Section: Resultssupporting

confidence: 90%

Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells

Kiritsy

Mott

Behar

et al. 2020

Preprint

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The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While toll-like receptor ligation relies on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNγ). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in macrophages to identify the regulators of IFNγ-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFNγ signaling pathway. We report that the IFNγ response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFNγ and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.

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Section: Resultssupporting

confidence: 90%

Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells

Kiritsy

Mott

Behar

et al. 2020

Preprint

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“…This result indicated that NKT cells are required for the activation of DCs, and the activation requires both a membrane-bound and a soluble factor. DCs and NKT cells can activate each other reciprocally through CD40-CD40-L binding, and IFNg increases CD40 expression by DCs (30). Results from the CD40-L blockade experiment confirmed that this molecule plays a critical role in the activation phase of the immune response.…”

Section: Discussionsupporting

confidence: 62%

Murine Splenic CD4+ T Cells, Induced by Innate Immune Cell Interactions and Secreted Factors, Develop Antileukemia Cytotoxicity

Nelles

Moreau

Furlonger

et al. 2014

Cancer Immunology Research

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Inciting the cellular arm of adaptive immunity has been the fundamental goal of cancer immunotherapy strategies, specifically focusing on inducing tumor antigen-specific responses by CD8 þ cytotoxic T lymphocytes (CTL). However, there is an emerging appreciation that the cytotoxic function of CD4 þ T cells can be effective in a clinical setting. Harnessing this potential will require an understanding of how such cells arise. In this study, we use an IL12-transduced variant of the 70Z/3 leukemia cell line in a B6D2F1 (BDF 1 ) murine model system to reveal a novel cascade of cells and soluble factors that activate anticancer CD4 þ killer cells. We show that natural killer T cells play a pivotal role by activating dendritic cells in a contactdependent manner; soluble products of this interaction, including MCP-1, propagate the activation signal, culminating in the development of CD4 þ CTLs that directly mediate an antileukemia response while also orchestrating a multipronged attack by other effector cells. A more complete picture of the conditions that induce such a robust response will allow us to capitalize on CD4 þ T-cell plasticity for maximum therapeutic effect.

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“…Cells treated with 5μg/ml insulin and 20 μg/ml EGF alone for 7 days served as controls. Extraction of membrane protein was as previously described with minor modifications [29]. Briefly, cells were harvested by centrifugation and re-suspended in homogenization buffer and were sonicated for 20 s on ice.…”

Section: Methodsmentioning

confidence: 99%

Insluin and epithelial growth factor (EGF) promote programmed death ligand 1(PD-L1) production and transport in colon cancer stem cells

et al. 2019

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Background Programmed cell death ligand 1 (PD-L1) is an important immune-inhibitory protein expressed on cancer cells to mediate cancer escape through interaction with PD-1 expressed on activated T lymphocytes (T cells). Previously, we reported that colon and breast cancer stem cells (CSCs) expressed much higher levels of PD-L1 than their parental cells, suggesting they will be more resistant to immune attack. Methods We investigated the underlining mechanism of PD-L1 increase in colon CSCs, with a special focus on the effect of insulin and epithelial growth factor (EGF), the two fundamental components to sustain the metabolism and stemness in the culture of CSCs. Results We found that insulin increased the total and surface PD-L1 levels through PI3K/Akt/mTOR pathway as the increase could be inhibited by the dual inhibitor of the pathway, BEZ235. EGF didn’t affect the total PD-L1 levels of CSCs but increased the cell surface protein levels by flow cytometry analysis, indicating EGF promotes the transport of PD-L1 to the cell surface. Blocking cell surface PD-L1 with a specific antibody resulted in a significant reduction of tumour sphere formation but didn’t interfere with the sphere growth, suggesting that cell surface PD-L1 may act as an adhering molecule for CSCs. Conclusions Apart from the essential roles in metabolism and stemness, insulin and EGF involve in up-regulation of PD-L1 expression in colon CSCs, therefore the inhibition of insulin and EGF/EGFR pathways can be considered for cancer immunotherapy or combined with PD-1/PD-L1 antibody-based cancer immunotherapy to eliminate CSCs.

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TNF-αPromotes IFN-γ-Induced CD40 Expression and Antigen Process in Myb-Transformed Hematological Cells

Cited by 10 publications

References 46 publications

Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells

Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells

Murine Splenic CD4+ T Cells, Induced by Innate Immune Cell Interactions and Secreted Factors, Develop Antileukemia Cytotoxicity

Insluin and epithelial growth factor (EGF) promote programmed death ligand 1(PD-L1) production and transport in colon cancer stem cells

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