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.

The Roles of 2-Hydroxyglutarate

“…Accumulated studies suggest that there is a close relationship between metabolism and the activation, differentiation, and exhaustion of immune cells ( Zhang and Romero, 2018 ; Yerinde et al, 2019 ). Some subsets of T cell exhibit a distinct metabolic feature.…”

“…For example, naïve CD8 + T cells metabolically rely on oxidative phosphorylation, and their activation leads to a metabolic switch to glycolysis, while memory T cells heavily depend on fatty acid oxidation ( Yerinde et al, 2019 ). Multiple processes of CD8 + T cells such as clonal expansion and memory formation are sustained by a distinct metabolic state ( Yerinde et al, 2019 ). Such association between metabolism and function also exists in other subsets of immune cells.…”

Metformin: Targeting the Metabolo-Epigenetic Link in Cancer Biology

“…Third, metformin can interact with diet/gut microbiota to systemically regulate the metabolic inputs to chromatin. However, despite the exciting progress in deciphering how metformin influences metabolically regulated epigenetic marks, we should acknowledge that mechanistic understanding of how it can reverse cancer-relevant functional outcomes [e.g., phenotypic plasticity and cell fate decisions in heterogenous cancer populations, metabolism-epigenome axes controlling anti-tumor immunity and immunotherapy efficacy (83)(84)(85)(86)(87)] by interfering with the metabolic regulation of the epigenome remains unsatisfactory.…”

The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment

“…During the last decade, studies on the epigenetic interplay between immune, stromal and cancer cells in the tumor microenvironment have emerged. These publications were particularly focused on the impact of epigenetics on the formation of CAFs (cancer associated fibroblasts) and CD8 T cell exhaustion (TOX) but more data on CD4 T cell biology need to be collected [57][58][59].…”