Distinct energy requirements for human memory CD4 T-cell homeostatic functions

Differentiation and activation of CD4 memory T cells (T_mem cells) require energy from different sources, but little is known about energy sources for maintenance and surveillance activities of unactivated T _mem cells. Mitochondrial fatty acid oxidation (FAO) in human unactivated CD4 T_mem cells was significantly enhanced by inhibition of glycolysis, with respective means of 1.7- and 4.5-fold for subjects <45 yr and >65 yr, and by stimulation of AMP-activated protein kinase, with respective means of 1.3- and 5.2-fold. However, CCL19 and sphingosine 1-phosphate (S1P), which control homeostatic lymphoid trafficking of unactivated T_mem cells, altered FAO and glycolysis only minimally or not at all. Inhibition of CD4 T_mem-cell basal FAO, but not basal glycolysis, significantly suppressed CCL19- and S1P-mediated adherence to collagen by >50 and 20%, respectively, and chemotaxis by >20 and 50%. Apoptosis of unactivated T_mem cells induced by IL-2 deprivation or CCL19 was increased significantly by >150 and 70%, respectively, with inhibition of FAO and by >110 and 30% with inhibition of glycolysis. Anti-TCR antibody activation of T_mem cells increased their chemotaxis to CCL5, which was dependent predominantly on glycolysis rather than FAO. The sources supplying energy for diverse functions of unactivated T_mem cells differ from that required for function after immune activation.