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

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 naive and memory (T_mem ) cells often rely on oxidative phosphorylation, and thus mitochondrial metabolism is a crucial determinant of CD8⁺ T_mem cell development. Moreover, it has been proposed that CD8⁺ T_mem 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 analyzing the metabolic characteristics of CD8⁺ T_mem cells, and emphasize how T cells exhibit flexibility in their choice of metabolic fuel.