Metabolic Control of Epigenetics and Its Role in CD8+ T Cell Differentiation and Function

Abstract

Epigenetic programs that control posttranslational modifications of histone proteins and DNA itself tightly regulate transcriptional networks determining the identity and function of CD8⁺ T cells. Chromatin-modifying enzymes such as histone acetyltransferases and deacetylases, represent key molecular determinants of the epigenetic imprinting of CD8⁺ T cells. The functions of these enzymes highly depend on the availability of key products of cellular metabolism pathways such as acetyl-CoA, NAD (Nicotinamide adenine dinucleotide) and SEM (S-adenosylmethionine), suggesting that there is a close crosstalk between the metabolic and the epigenetic regulation of CD8⁺ T cells. In this review, we will discuss the metabolic regulation of CD8⁺ T cell epigenetics during activation and differentiation. We will furthermore summarize how metabolic signals from the tumor microenvironment (TME) shape the epigenetic landscape of CD8⁺ T cells to better understand the mechanism underlying CD8⁺ T cell exhaustion in anti-tumor and anti-viral immunity, which might help to overcome limitations of current CD8⁺ T cell-based therapies.

Keywords: CD8 T cell; anti-tumor immunity; anti-viral immunity; epigenetics; exhaustion; metabolism.

Figure 1

Crosstalk between cellular metabolism and epigenetic changes. The function of epigenetic modifier enzymes depends on the intermediates or the products of cellular metabolism pathways resulting in epigenetic changes and therefore the transcriptional programs of the cells. Acetyl-CoA is the main source for histone acetylation leading to open and permissive chromatin structure. SAM is used by histone methyltransferases and demethylases. The function of sirtuin deacetylases depend on the availability of NAD. TCR-induced activation of pathways such as AMPK, mTOR, and AKT also contributes to the metabolic reprogramming of CD8⁺ T cells.

Figure 2

Comparison of CD8⁺ T cell differentiation and metabolism as well as epigenetic landscapes during infection and tumorigenesis. (A) Virus infection results in the activation of naïve CD8⁺ T cells triggering the differentiation into effector cells, which induce viral clearance. Subsequently, effector T cells contract and leave behind a small population of memory CD8⁺ T cells. During this differentiation process, CD8⁺ T cell subsets use the indicated cellular metabolism pathways and acquire different epigenetic landscapes specific to each phase. (B) In tumors, the presence of immunosupressive environments due to metabolic alterations in tumor cells results in an exhausted phenotype, in which tumor infiltrating T cells are not able to compete with tumor cells for metabolic products and they become non-functional resulting in increasing tumor growth. Exhausted T cells also acquire an exhaustion-specific epigenetic landscape.