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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

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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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Interleukin-10 causes interferon-γ-dependent emergency myelopoiesis

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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.

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

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

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