Transcriptional programing of T cell metabolism by STAT family transcription factors

T cells adapt their metabolism to meet the energetic and biosynthetic demands imposed by changes in location, behavior, and/or differentiation state. Many of these adaptations are controlled by cytokines. Traditionally, research on the metabolic properties of cytokines has focused on downstream signaling via the PI3K-AKT, mTOR, or ERK-MAPK pathways but recent studies indicate that JAK-STAT is also crucial. This review synthesizes current thinking on how JAK-STAT signaling influences T cell metabolism, focusing on adaptations necessary for the naive, effector, regulatory, memory, and resident-memory states. The overarching theme is that JAK-STAT has both direct and indirect effects. Direct regulation involves STATs localizing to and instructing expression of metabolism-related genes. Indirect regulation involves STATs instructing genes encoding upstream or regulatory factors, including cytokine receptors and other transcription factors, as well as non-canonical JAK-STAT activities. Cytokines impact a vast range of metabolic processes. Here, we focus on those that are most prominent in T cells; lipid, amino acid, and nucleotide synthesis for anabolic metabolism, glycolysis, glutaminolysis, oxidative phosphorylation, and fatty acid oxidation for catabolic metabolism. Ultimately, we advocate the idea that JAK-STAT is a key node in the complex network of signaling inputs and outputs which ensure that T cell metabolism meets lifestyle demands.

Automated summary

T cells adapt their metabolism to meet the energetic and biosynthetic demands, which is controlled by cytokines such as PI3K-AKT, mTOR, ERK-MAPK pathways, and JAK-STAT signaling. This review discusses how JAK-STAT influences T cell metabolism, focusing on adaptations required for naive, effector, regulatory, memory, and resident-memory states. JAK-STAT has both direct and indirect effects, regulating metabolism-related genes and instructing genes encoding upstream or regulatory factors. Cytokines impact various metabolic processes, including lipid, amino acid, and nucleotide synthesis, glycolysis, glutaminolysis, oxidative phosphorylation, and fatty acid oxidation.