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Acetate promotes T cell effector function during glucose restriction [RNA-seq]

ABSTRACT: Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here we show that acetate rescued effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promoted histone acetylation and chromatin accessibility, and enhanced IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increased IFN-γ production by exhausted T cells, while reducing ACSS expression in T cells impaired IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE128591 | GEO | 2019/05/14

REPOSITORIES: GEO

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Acetate promotes T cell effector function during glucose restriction [ChIP-seq]

Project description:Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here we show that acetate rescued effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promoted histone acetylation and chromatin accessibility, and enhanced IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increased IFN-γ production by exhausted T cells, while reducing ACSS expression in T cells impaired IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer.

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Acetate promotes T cell effector function during glucose restriction [ATAC-seq]

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Ionomycin Treatment Renders NK cells Hyporesponsive

Project description:Natural killer cells are cytotoxic lymphocytes important in immune responses to cancer and multiple pathogens. However, chronic activation of NK cells can induce a hyporesponsive state. The molecular basis of the mechanisms underlying the generation and maintenance of this hyporesponsive state are unknown, thus an easy and reproducible mechanism able to induce hyporesponsiveness on human NK cells would be very useful to gain understanding of this process. Human NK cells treated with ionomycin lose their ability to degranulate and secrete IFN-γ in response to a variety of stimuli, but IL-2 stimulation can compensate these defects. Apart from reductions in the expression of CD11a/CD18, no great changes were observed in the activating and inhibitory receptors expressed by these NK cells, however their transcriptional signature is different to that described for other hyporesponsive lymphocytes.

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A single intradermal injection of IFN-gamma induces a psoriasis-like state in both non-lesional psoriatic and healthy skin

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Transcription profiling of human umbilical vein endothelial cells treated with Interferon-gamma (IFN-g), Borrelia burgdorferi or both IFN-g and Borrelia or untreated to investigate immune responses to Lyme disease

Project description:Borrelia burgdorferi, the agent of Lyme disease, promotes pro-inflammatory changes in endothelium that lead to the recruitment of leukocytes. The host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. Therefore, the effect of IFN-gamma on the gene expression profile of primary human endothelial cells exposed to B. burgdorferi was determined. B. burgdorferi and IFN-gamma synergistically augmented the expression of 34 genes, seven of which encode chemokines. Six of these (CCL7, CCL8, CX3CL1, CXCL9, CXCL10, and CXCL11) attract T lymphocytes, and one (CXCL2) is specific for neutrophils. Synergistic production of the attractants for T cells was confirmed at the protein level. IL-1beta, TNF-alpha, and LPS also cooperated with IFN-gamma to induce synergistic production of CXCL10 by endothelium, indicating that IFN-gamma potentiates inflammation in concert with a variety of mediators. An in vitro model of the blood vessel wall revealed that an increased number of human T lymphocytes traversed endothelium exposed to B. burgdorferi and IFN-gamma, as compared to unstimulated endothelial monolayers. In contrast, addition of IFN-gamma diminished the migration of neutrophils across B. burgdorferi-activated endothelium. IFN-gamma thus alters gene expression by endothelium exposed to B. burgdorferi in a manner that promotes recruitment of T cells and suppresses that of neutrophils. This modulation may facilitate the development of chronic inflammatory lesions in Lyme disease. Experiment Overall Design: Human umbilical vein endothelial cells (HUVEC) were stimulated with Interferon-gamma (IFN-g), Borrelia burgdorferi or both IFN-g and Borrelia or were left unstimulated. Affymetrix HGU133 plus 2.0 slides were used in duplicate for each condition.

2008-06-14 | E-GEOD-6092 | biostudies-arrayexpress

Interferon-γ response against C. burnetii of peripheral blood mononuclear cells in the development of chronic Q fever

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2016-03-13 | GSE66476 | GEO

Interferon gamma down-regulates miR-3473b to promote macrophage activation

Project description:Macrophages are major effector cells and antigen presenting cells of the innate immune system and classical activation of macrophage function requires interferon–γ (IFN-γ) pretreatment (priming) and TLR stimuli, which promotes inflammatory responses though high levels of pro-inflammatory cytokines and lower level of the anti-inflammatory cytokines, resulting in microbicidal and tumoricidal effect. However, the underlying molecular mechanism of IFN-γ priming remains elusive. In this study, we explored the effect of IFN-γ on macrophages at miRNA level and discovered that miR-3473b, which was down-regulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. Molecular study revealed that miR-3473b promoted Akt/GSK3 signaling and IL-10 production through directly targeting PTEN to suppress inflammatory response and tumor-suppressing capability of macrophages. In summary, our data demonstrate that IFN-γ beef up macrophage inflammatory response and tumor suppressing capacity by limiting miR-3473b-mediated PTEN suppression. Our work identified an IFN-γ/miR-3473b/Akt axis in the regulation of macrophage function and activation. the assay was performed with 5 μg total RNA samples from both normal BMM (labeled by Cy3) and BMM primed by IFN-γ (100U/ml) for 4 h(labeled by Cy5), normal BMM serves as control.

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