Environmental Barriers to T Cell Metabolism and Function

Abstract

Immunometabolism describes the interface between immune cell function and metabolism. This interplay is governed by both cell-intrinsic metabolic programs that shape immune cell function, as well as environmental metabolites that, when scarce, can limit fuel choice and, when overabundant, can act as signaling molecules and alter cell fate and function. Here, we present two stories of how metabolites in the extracellular environment can directly impact T cell function. Fluctuations in environmental amino acid concentrations can dramatically alter T cell activity. Building on an observation made nearly 40 years ago showing that T cells fail to activate in the presence of dialyzed FBS, we demonstrate that the addition of a single amino acid, alanine, to dialyzed FBS is sufficient to restore T cell function. Therefore, we sought to investigate why T cells rely on extracellular alanine for their activation. We found that, once inside a T cell, alanine is not metabolized towards pyruvate but is instead directly shunted towards protein synthesis. In the absence of alanine, T cells fail to activate and proliferate due to a block in activation-induced protein synthesis. Thus, T cell activation may be influenced by local concentrations of alanine during physiological or disease states. In our second study, we investigate how metabolites in the tumor microenvironment can act as signaling molecules and suppress T cell function. Mutations in the metabolic gene isocitrate dehydrogenase result in the production of the oncometabolite D-2-hydroxyglutarete (D-2HG), which accumulates at high levels in the surrounding microenvironment. We demonstrate that D-2HG is taken up by CD8+ T cells and directly inhibits the activity of the glycolytic enzyme lactate dehydrogenase. This inhibition drives a metabolic program and a CD8+ T cell signature marked by decreased cytotoxicity and altered interferon gamma signaling that is recapitulated in clinical samples. Thus, we describe a novel role for the oncometabolite D-2HG in shaping anti-tumor immunity in the tumor microenvironment of IDH mutant cancers. Together, our studies highlight the role of metabolism in regulating T cell function and how alterations in metabolite levels in the surrounding environment can impact such regulation.