mTOR and lymphocyte metabolism

Abstract

Upon antigen engagement and proper co-stimulation, naïve lymphocytes exit quiescence and undergo clonal expansion and differentiate into functional effector cells, after which they either die through apoptosis or survive as memory cells. Lymphocytes at different activation stages exhibit distinct metabolic signatures. Emerging evidence highlights a central role for the mechanistic target of rapamycin (mTOR) in bridging immune signals and metabolic cues to direct lymphocyte proliferation, differentiation and survival. Here we review recent advances in understanding the functional significance and signal transduction of mTOR in T cell biology, and the interplay between mTOR signaling and metabolic programs.

Figure 1

T cells at different activation stages exhibit distinct metabolic phenotypes and mTOR activities. Naïve T cells rely on catabolism, particularly fatty acid β-oxidation, to maintain homeostasis. They also show low mTOR activity. Antigenic stimulation activates mTOR and markedly upregulates anabolic programs especially glycolysis and glutaminolysis, while downregulating fatty acid β-oxidation. The interplay between mTOR and metabolic programs collectively contributes to antigen-induced T cell growth and proliferation. Effector T cells maintain high glycolytic flux and mTOR activity, but their differentiation to memory T cells is accompanied by a metabolic switch from anabolism to catabolism, particularly upregulation of fatty acid β-oxidation, as well as downregulation of mTOR activity. A separate T cell lineage comprised of FOXP3⁺ T_reg cells also has high fatty acid β-oxidation but low/intermediate mTOR activities.

Figure 2

mTOR bridges immune signals and metabolic cues to regulate T cell responses. Multiple immune signals regulate mTOR activity, including TCR, costimulatory signals and cytokine receptors, as well as TLR, selective G protein-coupled receptors (GPCRs) and leptin receptors. Nutrients, such as amino acids and glucose, also mediate mTOR activation. These upstream inputs, through PI3K-AKT, JAK-STAT, and additional unidentified pathways, engage mTOR signaling. Once activated, mTOR shapes TCR and cytokine signaling through AKT and SOCS, and probably more importantly, reprograms metabolic activities including glycolysis through transcription factors MYC and HIF1. mTOR-dependent signaling pathways and metabolic programs are important regulators in T cell biology, including homeostasis, activation, lineage differentiation and memory formation. We propose that mTOR serves as a signal integration hub to bridge immune signals and metabolic cues, and the coordinated activation of these two major inputs by mTOR ensures proper execution of adaptive immunity in response to environmental signals