The Role of Glucose Metabolism in T Cell Stimulation and Homeostasis

Abstract

<p>The role of two cell extrinsic signals, T cell receptor (TCR) ligation and interleukin-7, in promoting glucose uptake and survival of T lymphocytes is examined in this work. Both of these signals are capable of regulating the uptake and fate of glucose, but the requirement of this regulation for T cell homeostasis and functionality remains unclear. To examine the role of TCR mediated increases of glucose metabolism and the signals involved, primary murine T cells were activated in vitro and the role and regulation of glucose uptake was examined. We show that glucose uptake is limiting in T cell activation and that CD28 costimulation is required for maximal glucose uptake following TCR stimulation by upregulating expression and promoting the cell surface trafficking of the glucose transporter Glut1. Regulation of T cell glucose uptake and Glut1 was critical, as low glucose prevented appropriate T cell responses. Additionally, transgenic expression of Glut1 augmented T cell activation, and led to accumulation of readily activated memory-phenotype T cells with signs of autoimmunity in aged mice. To further examine the regulation of glucose uptake, we analyzed CD28 activation of Akt, which appeared necessary for maximal glucose uptake of stimulated cells and which we have shown can promote Glut1 cell surface trafficking. Consistent with a role for Akt in Glut1 trafficking, transgenic expression of constitutively active Akt (mAkt) increased glucose uptake of resting T cells, but did not alter Glut1 protein levels. Therefore, CD28 appeared to promote Akt-independent upregulation of Glut1 protein and Akt-dependent Glut1 cell surface trafficking. In support of this model, co-expression of Glut1 and mAkt transgenes resulted in a synergistic increase in glucose uptake and accumulation of activated T cells in vivo that were largely independent of CD28. Induction of Glut1 protein and Akt regulation of Glut1 trafficking are therefore separable functions of CD28 costimulation that cooperate to promote glucose metabolism necessary for T cell activation and proliferation.</p><p>Glucose uptake is dramatically increased in response to TCR and costimulation signaling, however, glucose uptake must be maintained at a low level in naive T cells to promote survival and homeostasis. Interleukin-7 (IL-7) plays a central role in maintaining naive T cell homeostasis, and mediates this effect in vivo at least in part through control of homeostatic proliferation and inhibition of apoptosis. IL-7 can promote glucose uptake and glycolysis in vitro and may also promote glucose metabolism in vivo to maintain T cell survival. To determine if IL-7 regulates T cell metabolism in vivo, we generated a transgenic model for conditional IL-7 receptor (IL 7R) expression on IL-7R-/- T cells. T cells in this model developed normally and, consistent with previous work, deletion of the IL-7R transgene in vivo led to cell death even in an otherwise normal lymphoid compartment. Importantly, in vivo deletion of IL 7R also led to decreased cell size and glycolytic flux. However, glucose uptake was not altered following deletion of the IL-7R indicating that while not essential for glucose uptake, IL-7 is required for maintenance of glycolysis. These data are the first to identify a signal required in vivo to regulate lymphocyte metabolism and demonstrate that in addition to its well-defined roles in homeostatic proliferation and cell survival, IL-7 plays a key and non-redundant role to maintain T cell glycolysis. Together, these data concerning the role of TCR, costimulation, and IL-7 in the regulation of glucose uptake and metabolism exemplify the importance of cell extrinsic signals and the regulation of glucose utilization.</p>