Therapeutic opportunities to modulate immune tolerance through the metabolism-chromatin axis

Metabolic and epigenetic events control T cell differentiation and function to ensure immune competence while avoiding immune pathology. Small metabolic intermediates can switch in parallel energy metabolism and gene expression. Intracellular metabolism and chromatin modifications converge to finely tune Foxp3 transcription. Immune-related disorders display metabolic and epigenetic alterations. Epigenetic therapies are a novel attractive tool to restore immune tolerance through metabolism. The ability of the immune system to discriminate external stimuli from self-components – namely immune tolerance – occurs through a coordinated cascade of events involving a dense network of immune cells. Among them, CD4+CD25+ T regulatory cells are crucial to balance immune homeostasis and function. Growing evidence supports the notion that energy metabolites can dictate T cell fate and function via epigenetic modifications, which affect gene expression without altering the DNA sequence. Moreover, changes in cellular metabolism couple with activation of immune pathways and epigenetic remodeling to finely tune the balance between T cell activation and tolerance. This Review summarizes these aspects and critically evaluates novel possibilities for developing therapeutic strategies to modulate immune tolerance through metabolism via epigenetic drugs. The ability of the immune system to discriminate external stimuli from self-components – namely immune tolerance – occurs through a coordinated cascade of events involving a dense network of immune cells. Among them, CD4+CD25+ T regulatory cells are crucial to balance immune homeostasis and function. Growing evidence supports the notion that energy metabolites can dictate T cell fate and function via epigenetic modifications, which affect gene expression without altering the DNA sequence. Moreover, changes in cellular metabolism couple with activation of immune pathways and epigenetic remodeling to finely tune the balance between T cell activation and tolerance. This Review summarizes these aspects and critically evaluates novel possibilities for developing therapeutic strategies to modulate immune tolerance through metabolism via epigenetic drugs. lack of reaction by the immune system to a particular antigen or allergen. an organic compound that provides energy to drive many processes in living cells. a transcription factor playing an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens. an intracellular degradation system wherein damaged organelles, unneeded proteins, as well as pathogenic agents, are digested and the resulting macromolecular content is released back into the cytosol. the catabolic process by which fatty acid molecules are broken down in the mitochondria to generate acetyl-CoA, which enters the citric acid cycle, and NADH and FADH2, which are coenzymes used in the electron transport chain. a family of small cytokines or signaling proteins that promotes directional movement of cells. the anchor points providing contacts between regulatory regions and promoters. short region of DNA with high frequency of the CG sequence, often located around gene promoters. a protein that acts inducing modifications of DNA and gene expression without affecting gene sequence. the polynucleotide sequence of the nucleic acid coding information for protein synthesis. the mitochondrial aerobic process of breaking down a fatty acid into acetyl-CoA units (see β oxidation). cytoplasmic pathway that breaks down glucose into two three-carbon compounds (pyruvate) and generates energy. a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. the finely regulated balance of appropriate immune activation and suppression in tissues and organs. also known as antibodies; glycoproteins produced by B lymphocytes that bind and neutralize particular antigens, such as bacteria or viruses. a branch of biology that studies the interplay between metabolism and immunology in all organisms. the receptors able to prevent the cell from receiving proper activation signals. a stromal cell population of the thymus which plays an essential role in the establishment of tolerance. an electron transfer chain driven by substrate oxidation that is coupled to the synthesis of ATP within the inner membrane of the mitochondria. a quiescent cell not undergoing mitosis. antigens of an organism, such as cellular proteins, peptides, ribonucleoprotein complexes and DNA, to which the immune system is tolerant. the alternative forms of mRNA derived from a single gene sequence. subsets of CD4 T cells that play an important role in adaptive immunity. a series of chemical reactions used in aerobic organisms to generate energy via the oxidation of acetyl-CoA derived from carbohydrates, fatty acids and proteins. a metabolic pathway in which the amino acids arginine, ornithine and methionine are decarboxylated by ornithine decarboxylase to generate putrescine, spermidine, and spermine. the system surrounding a tumor including several types of immune cells, the extracellular matrix, blood vessels and other biochemical and cellular components in direct contact with cancer cells. branches from glucose 6-phosphate, produces NADPH and ribose 5-phosphate, and shunts carbons back to the glycolytic or gluconeogenic pathway.