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Metabolic control of T-cell immunity via epigenetic mechanisms

Cellular & Molecular Immunology volume 15, pages 203–205 (2018)Cite this article

Metabolism has been increasingly considered to play an important role in inflammation and immunity via modulating cellular signaling and transcriptional networks.1 Dysregulation of metabolic enzymes or mediators is increasingly linked to clinical diseases, such as type I diabetes, gliomas and breast cancer.2, 3 Numerous metabolic sensors, such as AMP-mediated protein kinase, mammalian target of rapamycin complex1 and hypoxia-induced factor 1α (HIF-1α), have been shown to regulate immunological responses, such as T-cell activation and macrophage polarization, via modulating the property and activity of signaling pathways.4, 5 Moreover, emerging evidence suggests that intermediates from multiple metabolic pathways are important in orchestrating transcriptional and epigenetic programs. This interaction between metabolic and epigenetic pathways is crucial for coordinating cellular immunological events in response to extracellular stimuli, such as infection, injury and stress, leading to varied biological and pathological outcomes.

Epigenetic mechanisms include multi-level intracellular events that influence chromatin structure and gene expression without altering DNA sequences, such as DNA methylation, post-translational modifications of histones, non-coding RNAs and chromatin remodeling. Importantly, intermediary metabolites can serve as the substrates, cofactors or inhibitors of epigenetic enzymes to affect gene expression and thus influence variable biological processes, such as long-term memory, muscle function, stem cell differentiation and tumorigenesis.6, 7, 8 Acetyl-CoA is produced in various metabolic pathways and serves as an acetyl group donor of histone acetyltransferase, which is the critical step of acetylation.6 Nicotinamide adenine dinucleotide (NAD+) produced from nicotinamide mononucleotide is required for deacetylation mediated by Sirtuin family histone deacetylases.7 Likewise, S-adenosylmethionine and α-ketoglutarate (α-KG) are respectively required for DNA/histone methylation (catalyzed by DNA methyltransferase and histone methyltransferases) or demethylation (catalyzed by ten-eleven translocation and jumonji C -domain-containing enzymes).8 Other examples of metabolites that regulate epigenetic pathways include crotonyl-CoA for histone crotonylation9 and UDP-GlcNAc for histone GlcNAcylation.10 These connections between cellular metabolism and epigenetic mechanisms lead to multi-level modulation of gene transcription and cell signaling, exerting important roles in cell development and function. While cellular immunological responses are accompanied by dynamic alterations and interactions of cellular metabolic and epigenetic pathways, how these two key biological pathways interplay to feedback modulate immune cell function during infectious or stress conditions is attracting more and more attention.

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Authors and Affiliations

  1. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China

    Xiaomin Zhang, Juan Liu & Xuetao Cao

  2. Department of Immunology and Center for Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China

    Xuetao Cao

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Correspondence to Xuetao Cao.

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Zhang, X., Liu, J. & Cao, X. Metabolic control of T-cell immunity via epigenetic mechanisms. Cell Mol Immunol 15, 203–205 (2018). https://doi.org/10.1038/cmi.2017.115

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