Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism.

A characteristic of memory T (T_M) cells is their ability to mount faster and stronger responses to reinfection than naïve T (T_N) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 T_Mcells have more mitochondrial mass than CD8 T_Ncells and, that upon activation, the resulting secondary effector T (T_E) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, T_Mcells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than T_Ncells, suggesting that greater mitochondrial mass in T_Mcells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both T_Nand T_Mcells. We also found that fatty acid oxidation is needed for T_Mcells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in T_Mcells. Our results demonstrate that greater mitochondrial mass endows T_Mcells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection.