Metabolic Control of Memory T-Cell Generation and Stemness

Abstract

The formation of long-lived memory T cells is a critical feature of the adaptive immune response. T cells undergo metabolic reprogramming to establish a functional memory population. While initial studies characterized key metabolic pathways necessary for memory T-cell development, recent findings highlight that metabolic regulation of memory T-cell subsets is diverse. Here we describe the different requirements for metabolic programs and metabolism-related signaling pathways in memory T-cell development. We further discuss the contribution of cellular metabolism to memory T-cell functional reprogramming and stemness within acute and chronic inflammatory environments. Last, we highlight knowledge gaps and propose approaches to determine the roles of metabolites and metabolic enzymes in memory T-cell fate. Understanding how cellular metabolism regulates a functionally diverse memory population will undoubtedly provide new therapeutic insights to modulate protective T-cell immunity in human disease.

Figure 1.

Metabolic pathways and metabolism-associated signaling in memory T cells. T-cell receptor (TCR), costimulatory molecule CD28, and cytokine receptor (e.g., IL-2 receptor and IL-15 receptor) signals induce mTORC1 and mTORC2 activation via PI3K-Akt signaling (Chi 2012). mTORC1 promotes glycolysis and other anabolic programs to invoke effector T-cell responses (Zeng et al. 2016; Tan et al. 2017; Chapman et al. 2020), while low mTOR signaling favors memory T-cell development and maintenance due to increased FoxO1/3a transcriptional activity and catabolic mitochondrial metabolism (Araki et al. 2009; Rao et al. 2012; Hess Michelini et al. 2013; Pollizzi et al. 2015; Delpoux et al. 2018; Utzschneider et al. 2018). High AMPK signaling regulated by extracellular ATP (eATP) and intracellular ADP/AMP:ATP ratio also favors memory T-cell development by limiting mTORC1 signaling and promoting fatty acid oxidation (FAO) and mitochondrial oxidative phosphorylation (OXPHOS) driven by the electron transport chain (ETC) (Rolf et al. 2013; Borges da Silva et al. 2018). Triacylglyceride (TAG) synthesis from extracellular glucose or glycerol may generate long-chain fatty acids (LCFAs), or LCFAs may be transported from extracellular sources to increase the intracellular fatty acid pool. These LCFA can be transported via FABP4/5 to fuel CPT1a-dependent FAO in specific contexts (Cui et al. 2015; Pan et al. 2017). Both FAO and aerobic glycolysis allow for generation of acetyl coenzyme A (acetyl-CoA), which enters the tricarboxylic acid (TCA) cycle to support ATP production for memory T cells (Pearce et al. 2009; van der Windt et al. 2012; Maekawa et al. 2015; Phan et al. 2016) and promotes mitochondrial metabolism that poises cells for rapid secondary responses (van der Windt et al. 2012, 2013; Buck et al. 2016; Klein Geltink et al. 2017). Acetyl-CoA also likely contributes to epigenetic remodeling (Peng et al. 2016). The amino acids serine and methionine may contribute to mitochondrial one-carbon metabolism to promote memory T-cell generation or proliferation via purine synthesis and epigenetic remodeling. Red inhibitory arrows indicate suppression of mTORC1, CPT1a, and the ETC by rapamycin, low-dose etomoxir, and high-dose etomoxir, respectively. The green arrow indicates activation of AMPK by metformin. Dashed arrows indicate that parts of the pathway are omitted. (ADP) Adenosine diphosphate, (AMP) adenosine monophosphate, (AMPK) AMP-activated protein kinase, (AQP9) aquaporin 9, (ATP) adenosine triphosphate, (CPT1a) carnitine palmitoyl transferase, (FABP4/5) fatty acid–binding protein 4 and 5, (FoxO1/3a) Forkhead box O1 or 3a, (mTORC1) mechanistic target of rapamycin (mTOR) complex 1, (mTORC2) mTOR complex 2, (PI3K) phosphatidylinositol 3-kinase.

Figure 2.

Metabolic reprogramming in memory T-cell subsets. Naive T (Tn)-cell activation, proliferation, and differentiation into effector T cells (Teff) require the up-regulation of mTORC1 signaling and switch to anabolic metabolism (Chapman et al. 2020). Among Teff are terminal effector precursor cells with high anabolic programs that will undergo apoptotic-mediated death and memory precursors with catabolic programs that can survive contraction and develop into memory T cells. The development of memory T cells is associated with entering into a quiescent state with elevated catabolic metabolism, a switch that relies on up-regulated AMPK (adenosine monophosphate-activated protein kinase) signaling and down-regulated mTOR (mechanistic target of rapamycin) signaling (Araki et al. 2009; Pearce et al. 2009; Kaech and Cui 2012; Pollizzi et al. 2015). Memory T cells comprise subsets with diverse requirements for metabolic programs, nutrients, and metabolites. There are context-dependent roles for aerobic glycolysis and mitochondrial metabolism in CD8⁺ and CD4⁺ memory T-cell subsets (van der Windt et al. 2012, 2013; Maekawa et al. 2015; Buck et al. 2016; Phan et al. 2016; Klein Geltink et al. 2017). Memory T cells require fatty acid oxidation (FAO) to support mitochondrial metabolism, cell survival, and function, but the dependency on FAO and source of fatty acids, including glycerol-mediated triacylglyceride (TAG) synthesis, varies among subsets and tissue localization (Pearce et al. 2009; van der Windt et al. 2013; O'Sullivan et al. 2014; Cui et al. 2015; Pan et al. 2017; Raud et al. 2018). Extracellular ATP (eATP) enhances mitochondrial metabolism and promotes central memory (Tcm) and tissue-resident memory (Trm) development (Borges da Silva et al. 2018). mTORC1 signaling and up-regulation of glycolytic metabolism may also promote maturation and loss of cellular stemness (Karmaus et al. 2019). (Tem) Effector memory, (T stem-like) stem-cell-like memory T cell.