Transcriptional programing of T cell metabolism by STAT family transcription factors

Abstract

AbstractT 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 naïve, 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.