Decipheringthe role of alanine as a novel metabolic regulator of T cell immunity
Abstract:
T lymphocytes survey our body for threats. Under homeostasis, thesecells rarely proliferate. Upon encountering their cognate antigen and dangersignals, within hours, they enter a phase of robust proliferation to generatean army of lymphocytes to fight the threat. These rapid changes require reprogramming the cell’s metabolism. Indeed,as T cells get activated, they simultaneously induce multiple anabolic pathwaysto induce biomass production and effector functions. Such metabolicreprogramming relies on extracellular pools of precursor nutrients, includingglucose and amino acids. Even amino acids that are otherwise considered‘non-essential’. Recently, we identified alanine as an essential amino acid forT cells during early activation. This finding was surprising especially sincealanine is a non-essential amino acid that can be made by a one-step reactionfrom pyruvate, a product of glycolysis, one of the most highly induced pathwaysin activated T cells. In agreement, we found that glutamate pyruvatetransaminase (GPT), the enzyme catalyzing alanine production was not expressedin T cells, even when deprived of alanine. We hypothesized that T cellspurposefully suppress GPT expression and rely on extracellular alanine toenable pyruvate flux into other metabolic pathways. In this study, we testedthis hypothesis by overexpressing GPT in primary T cells and examining itseffect on T cells’ metabolism and function. We found that GPT overexpressionrescued growth, activation, and proliferation of T cells grown in alanine-deprivedmedia but decreased cell viability. Furthermore,GPT overexpression caused significant changes in cellular metabolic flux andmetabolite concentrations. Future studies will investigate how these metabolicshifts could affect T cell functions.
