Fatty acid metabolism in CD8⁺ T cell memory: Challenging current concepts

Abstract

Fatty acid metabolism in CD8+ T cell memory CD8+ T cells are key members of the adaptive immune response against infections and cancer. As we discuss in this review, these cells can present diverse metabolic requirements, which have been intensely studied during the past few years. Our current understanding suggests that aerobic glycolysis is a hallmark of activated CD8+ T cells, while naïve and memory (Tmem) cells often rely on oxidative phosphorylation, and thus mitochondrial metabolism is a crucial determinant of CD8+ Tmem cell development. Moreover, it has been proposed that CD8+ Tmem cells have a specific requirement for the oxidation of long-chain fatty acids (LC-FAO), a process modulated in lymphocytes by the enzyme CPT1A. However, this notion relies heavily on the metabolic analysis of in vitro cultures and on chemical inhibition of CPT1A. Therefore, we introduce more recent studies using genetic models to demonstrate that CPT1A-mediated LC-FAO is dispensable for the development of CD8+ T cell memory and protective immunity, and question the use of chemical inhibitors to target this enzyme. We discuss insights obtained from those and other studies analysing the metabolic characteristics of CD8+ Tmem cells, and emphasise how T cells exhibit flexibility in their choice of metabolic fuel.

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

“…Thus, T cells exiting quiescence increase anabolic pathways and their intermediates can be used for synthesis or enter the TCA cycle to fuel mitochondrial OXPHOS(Figure 1 bottom). In contrast, Treg and Tm use OXPHOS and FAO, with emerging reports indicating T cells are more metabolically flexible than previously thought 271. These findings indicate distinct T cell subtypes use different metabolic pathways.…”

“…Several studies of mitochondrial dynamics indicate FAO is a pivotal regulator of Tm fate. 271 Antigen-specific CD8 Tm development is dependent on TRAF6-regulated lipid metabolism and TRAF6 deficiency resulted in defective AMPK activation and diminished FAO. 279 Furthermore, mice with T cells lacking TRAF6 have excessive cytokine production, suggestive of an abnormal Th effector response.…”

The metabolic spectrum of memory T cells

“…The importance of LC‐FAO for memory T‐cell development, has recently been challenged by a study using mice with a T cell‐specific deletion of CPT1a . Furthermore, the use of etomoxir, a CPT1 inhibitor, used extensively in studies assessing LC‐FAO, was demonstrated in multiple contexts to have off‐target effects that could cloud the interpretation of findings relying on etomoxir to inhibit CPT1a . In contrast to previous studies that used either genetic overexpression, hairpin or siRNA‐mediated knockdown, or drug inhibition of CPT1a, Raud et al .…”

“…61 Furthermore, the use of etomoxir, a CPT1 inhibitor, used extensively in studies assessing LC-FAO, was demonstrated in multiple contexts to have off-target effects that could cloud the interpretation of findings relying on etomoxir to inhibit CPT1a. 61,65,66 In contrast to previous studies that used either genetic overexpression, hairpin or siRNA-mediated knockdown, or drug inhibition of CPT1a, Raud et al 61 used a Cpt1aflox-CD4 Cre conditional deletion to specifically delete CPT1a in T cells. They provide convincing evidence that CD8 + T cells from these mice survive and establish a secondary effector response to L. monocytogenes infection thus calling into question the requirement for CPT1a in memory T-cell function.…”

The clock is ticking: the impact of ageing on T cell metabolism

“…Key substrates for the TCA cycle can be derived from fatty acids and amino acids. Specifically, resting T cells can use FAO (beta oxidation) to fuel the TCA cycle (Figure ). Fatty acids are transported into the mitochondrial matrix by a complex containing carnitine palmitoyltransferase Ia, where they undergo FAO to generate acetyl‐CoA that can enter the TCA cycle.…”