EPIGENETIC CONTROL OF T‐CELL ACTIVATION
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| Figure 7.15 “Pioneer” factors can establish an enhancer landscape to facilitate gene expression. (a) Prior to T‐cell activation, chromatin around gene enhancer regions remains in a conformation that is closed for gene transcription. (b) Following stimulation, “pioneer” transcription factors are recruited to enhancer regions. (c) Pioneer factors can displace the chromatin directly or recruit histone‐modifying enzymes such as histone acetyltransferases (HAT) for this purpose, creating an open conformation for gene transcription. (d) Transcription factors (TF) can now bind and activate RNA polymerase II‐mediated gene transcription. |
Epigenetic control of gene expression regulates T‐cell activation and differentiation
Activation and differentiation of T‐cells into the correct effector subsets is fundamental to generating an immune response capable of fighting a specific infection. Accordingly, the genes controlling T‐cell activation and differentiation are tightly controlled. Nuclear DNA is normally wrapped around proteins called histones, which act as spools around which DNA winds, allowing the cell to compact and order a large amount of genetic information into the relatively small confines of the nucleus. Importantly, histones act as guardians of genetic information by shielding genes from activating transcription factors and as such, histone modification introduces a important layer of regulation of gene expression. For example, posttranslational modifications of histones at specific amino acids may directly change the conformation of histone at that site and effectively loosen or tighten its grip on DNA, thereby making it more or less accessible for transcription factor binding and gene activation. This can also occur indirectly, where histone modification creates a binding site for chromatin‐modifying factors, which can then change the structure of chromatin to activate or repress gene transcription at a particular locus. ChIP‐sequencing (Chip‐Seq) is an experimental technique that combines chromatin immunoprecipitation with large‐scale DNA sequencing to detect binding sites between proteins and DNA on a genome‐wide scale. This technology has uncovered many important histone modifications, including trimethylation of histone H3 at lysine 4 (H3K4me3), which promotes an active chromatin arrangement at particular genes, and H3K27me3, which may tighten chromatin and repress gene transcription. In addition, direct methylation of DNA at CpG sites may render genes less transcriptiona ly active and this can play an important role in gene regulation.
ACTIVATED T‐CELLS UNDERGO AN ESSENTIAL METABOLIC SHIFT
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Figure 7.16 Metabolic pathways driving growth and proliferation. Glycolysis and the tricarboxylic acid (TCA) cycle function separately and in combination to generate ATP and biosynthesis‐promoting metabolites. Glucose is first broken down into pyruvate, which can then be converted to NAD+ and used to re‐start glycolysis. A small amount of pyruvate can also be used as a source of acetyl‐CoA to drive the TCA cycle in mitochondria. Intermediates from the glycolysis pathway can be siphoned off and used by the pentose phosphate pathway to produce ribose‐5P and by the serine biosynthesis pathway to generate serine, both of which can be used to make nucleotides. Citrate can be removed from the TCA cycle and used to regenerate acetyl‐CoA for lipid biosynthesis. To keep the TCA cycle moving in the absence of citrate, glutamine is converted to glutamate through glutaminolysis, and then to α‐ketoglutarate, to re‐enter the cycle. Oxaloacetate can also be used to generate aspartate for nucleotide synthesis.
Metabolic reprogramming drives T‐cell activation and effector differentiation
It should now be apparent that lymphocyte activation triggers a myriad of signaling pathways that radically transform resting T‐cells in preparation for effector function, and recent developments have uncovered a crucial role for specific metabolic pathways in not only fueling these changes, but in directing the outcome of T‐cell differentiation into specific effector subtypes. Activated T‐cells not only differ metabolically from their quiescent counterparts, differentiation into the various effector populations cannot proceed without distinct metabolic reprogramming.
METABOLIC CONTROL OF T‐CELL
DIFFERENTIATION
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| Figure 7.17 Regulation Of T‐Cell Differentiation And Metabolism By Transcription Factors. T‐Cell Specific Metabolic Signatures Essential For Function, And Maintenance Of T‐Cell Subset, Are Driven By The Action Of Key Transcription Factors. |
It should now be clear that metabolic reprogramming plays a crucial role in T‐cell activation. However, the regulation does not end there. Specific metabolic programs are not only essential for the immune‐stimulatory function of particular T‐cell subsets, the individual nature of the metabolic signal also plays a crucial role in determining differentiation to the extent that inhibiting one metabolic signal over another is sufficient to shunt T‐cell differentiation towards a different outcome. Genetic studies have revealed an essential role for the mTOR pathway in promoting Th1, Th2, and Th17 differentiation, with stimulation of mTOR‐deficient cells leading mainly to differentiation of Tregs, which outlines a crucial role for mTOR in promoting effector T‐cell (Teff ) differentiation (Figure 7.17). Indeed, the layers of mTOR regulation extend to individual effector Th populations, with deletion of the mTORC1 activator Rheb biasing toward the Th2 effector cell phenotype while deletion of RICTOR, an essential component of the mTORC2 complex, favors generation of mainly Th1 and Th17 effectors (Figure 7.17). Thus, mTORC1 activation directs differentiation towards Th1 and Th17, while mTORC2 promotes Th2 production. While mTOR activation can skew towards Th1 or Th2 phenotypes, HIF1α has a particularly important role in the differentiation of Th17 cells by activating the Th17‐specific master transcription factor RORγt. In addition, HIF1α can also bind the Treg‐specific master regulator Foxp3, promoting its degradation and the inhibition of Treg differentiation. As such, genetic deletion of HIF1α blocks Th17 responses and skews differentiation to Treg cells.
THE HANDLING OF ANTIGEN
Figure 6.18 Interdigitating dendritic cells (IDCs). (a) Scanning electron micrograph of a veiled cell, the morphological form adopted by IDCs as they travel in the afferent lymph. (Source: Image courtesy of G.G. MacPherson.) (b) IDC in the thymus‐dependent area of the rat lymph node. Intimate contacts are made with the surface membranes (arrows) of the surrounding T‐lymphocytes (TL) (×2000). In contrast to these IDCs that present processed antigen to T‐cells, the follicular dendritic cells in germinal centers present intact antigen to B‐cells.
